COMPUTATIONAL CHEMISTRY438 Doi:10.2533/Chimia.2007.438 CHIMIA 2007, 61,No

MEDICINAL CHEMISTRY/COMPUTATIONAL CHEMISTRY438 doi:10.2533/chimia.2007.438 CHIMIA 2007, 61,No. 7/8

Medicinal Chemistry 85 Medicinal Chemistry 86

NewC-glucosylxanthones from theleaves of Arrabidaea patellifera Analyses andbioactivitiesofwildpopulations of Rhodiola rosea L. (Bignoniaceae) (Crassulaceae) from Switzerland

F. Martina ,A.E.Haya ,S.Vargas a ,L.Vivasb ,M.P.Guptac and D. van Diermen, A. Marston, K. Ndjoko and K. Hostettmann K. Hostettmanna,* LaboratoryofPharmacognosyand Phytochemistry, School of Pharmaceuti- a LaboratoryofPharmacognosyand Phytochemistry, School of Pharmaceuti- cal Sciences,University of Geneva, University of Lausanne, Quai Ernest- cal Sciences,University of Geneva, University of Lausanne, Quai Ernest- Ansermet30, CH-1211 Geneva 4, Switzerland Ansermet30, CH-1211 Geneva 4, Switzerland. b London School of Hygiene and Tropical Medicine, Department of Infec- tious and Tropical Diseases,Keppel Street, LondonWC1E7HT,UK Rhodiola rosea L.,alsoknown as Golden root, hasbeen used forcenturies c Center forPharmacognostic Research on Panamanian Flora in the traditionalmedicine of EasternEurope and Asia. It has been classed (CIFLORPAN), College of Pharmacy,University of Panama,Panama as an adaptogenbyRussian researchersdue to its ability to increaseresis- tance in humans to avariety of stressors. As apartofour ongoing investigations on Panamanian Bignoniaceae [1], According to the Soviet Pharmacopoeia(RFMHMI 1983),extracts of sevenmethanolic extractsfrom sixplantsweresubmittedtoa -hematin Rhodiola rosea L. arenow standardized in both rosavin (min. 3%)and sa- polymerization inhibition test[2].This reaction is one of the possible targets lidroside(min.1%) content [1]. in the fight againstparasites of the genus Plasmodium,responsible forma- Theefficacy observed in clinical studies is due to thesynergistic activity of laria. Theextract fromthe leaves of Arrabidaeapatellifera (Schlecht) these two metabolitesand otheractive ingredients. Sandw.,aliana which grows fromlowlands to mountainforest, wasselected An efficient analytical method by HPLC-UV/DADwas developedtoquan- becauseofits good activity, corroborated by an in vitro test against Plasmo- tifyrosavin and salidrosideinthe roots of four wild populations of R. rosea dium falciparum.Moreover,this plant has never been investigated before. L. comingfromthe same area in Switzerland. Theanalyses wereperformed Theextract was firstfractionated by vacuumliquidchromatography (VLC) in order to observe the variability in the populations,and to establishthe and then by medium pressure liquid chromatography (MPLC).Itafforded dynamicsoftheir rosavin and salidroside content over aone year period. directly mangiferin and four of its derivatives,new C-glucosylxanthones, all Theresults obtainedafter the analysis of 20 sampleswill be useful in the active in vitro against P. falciparum.Further chromatographic separations selection of the mostappropriate population forlarge scale cultivation. gave other compounds,ofwhich theidentificationisunderway. Acetylcholinesterase-inhibitory activity was observed due to the presence in Thestructures were determined by meansofspectrometric methods,includ- theplant of linoleic acidand cinnamic alcohol. ing 1D and 2D NMRexperiments and MS analysis. Further investigations on R. rosea areunderwayinorder to discover new biological activities, especially in the area of depression (inhibition of [1] F. Martin, A.E. Hay, L. Corno, M. P. Gupta,K.Hostettmann, Phyto- monoamine-oxidase). chemistry. 2007,inpress [2]K.K.Ncokazi, T. J. Egan, Anal.Biochem. 2005, 338 ,306-319 [1]Khanum F.,BawaA.S., Singh B ., Comp RevFood Sci Food Safety, 2005, 4 ,55-62.

Medicinal Chemistry 87 Computational Chemistry 88

ANew Protocol to theSyntheses of , -Diamino Acids DFT Study of Jahn-Teller Eﬀect in Cobaltocene

Y. Liu 1 ,P.Schmutz1 ,M.Bauwens2 ,J.Mertens2 ,R.Alberto1 Matija Zlatar1 , 2 ,Emmanuel PenkaFowe1 ,Carl-Wilhelm Schlapfer1 , Claude Daul1 1 Institute of Inorganic Chemistry, University of Zurich Winterthurerstr. 190, 1 CH-8057 Zurich,Switzerland 2 Radiopharmaceutical Chemistry, DepartmentofChemistry,UniversityofFribourg, Chemin de Musé e9, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussel, Belgium CH-1700, Fribourg, Switzerland 2 Center for Chemistry,IHTM, UniversityofBelgrade, Njegoˇs eva12, P.O. Box815, 11001 Belgrade, Serbia , -Diamino Acids have attracted the interests from both organic chemists and biochemists through years,becauseofits unique structural and ubiqui- The detailed analysis of Jahn-Teller (JT) effect in bis -cyclopentadyenyl- tous role playing in biologically active compounds.Moreover,ithas been cobalt(II) -cobaltocene (CoCp2 ), is given. Descentinsymmetry goes from demonstratedthatthe , -diamino acid can be used as efficient tripodal D 5 h (eclipsed conformation of the two rings) to C 2 v .The electronic ground ligand forthe labelling of Re(I)/Tc(I) tricarbonyl,the corresponding hydro- 2 2 2 state, E 1 ,splits into A 2 and B 1 .Wehave used the methoddeveloped by philic compound of which is stable to air and competition fromcysteine or Daul et al. [1] for the calculation of the ground-state JT stabilization energy histidine. However,inthe radiopharmaceutical context, only after being ( E JT)and the resulting properties of aJT-activemolecules by DFT. The adi- coupled to otherbiomolecules,could , -diaminoacids be feasible for the abatic potential energy surface is described by three parameters ( E JT,Δand further application[1]. R JT)whichare related to the Bersuker’s description [2] of E ⊗ e problem ( K E , Herewereportanew method forthe preparation of , -diamino acid, F E , G E -force constant, first and second order vibronic coupling constants − 1 which entails alsothe convenientsynthesesof , -diamino acids derivat- respectively). We obtained E JT =750 − 850 cm (depending on the basis ized at -position. Thedeprotected 2 formedstableRe(I)/Tc(I)tricarbonyl set and functional used) whichisinagreementwith experimentally estimated complex, whichcan be recognized and transported into acell by LAT1 [2]. value of 1010 cm− 1 [3]. There is no second order JT effect. The geometry changed mainly in the Cp rings. The results are interpreted by group theory, NHCbz NHCbz in both, the high, D ,and the low, C 2 v ,symmetry.In D ,the problem NHBoc 5 h 5 h a) CN MsO COOEt a) wasconsidered as amultimode E ⊗ ( e )and in a C as amultimode BocHN COOEt i i 2 v b) 2 2 AcHN COOEt AcHN COOEt AcHN COOEt ( A 2 + B 1 ) ⊗ ( i a i )vibronic interactions. The contribution of the totally 1 2 symmetrical vibrations in C to the E wasanalysed. o 2 v JT a) NaBH4 ,NiCl 2 ,Boc2 O, MeOH,0C; b) NaOEt, EtOH,reflux [1] R. Bruyndockx, C. Daul, P. T. Manoharan, E. Deiss, Inorg. Chem., [1]R.Alberto, Top. Curr. Chem., 2005, 252,1-44. 1997, 36,4251-4256. [2]Y.Liu,J.K.Pak,P.Schmutz,M.Bauwens, J. Mertens, H. Knight,R. [2] I. B. Bersuker, The Jahn-Teller Effect,Cambridge University Alberto, J. Am.Chem. Soc., 2006, 128, 15996-15997. Press, 2006. [3] R. Bucher, ESR-Untersuchungen an Jahn-Teller-Aktiven Sand- witchkomplexen,PhD Thesis, ETH Zuerich, 1977. COMPUTATIONAL CHEMISTRY439 CHIMIA 2007, 61,No. 7/8

Computational Chemistry 89 Computational Chemistry 90

Equilibrium geometries of non-covalently bound intermolecular Electronic Structureofthe Ni/-Al 2 O 3 Catalyst: DFTCluster ModelStudy complexes derived from subsystem formulation of density functional theory IzabelaCzekaj,JörgWambach, Alexander Wokaun Marcin Dulaka ,Jakub W. Kamiń skia,b and Tomasz A. Wesolowskia Paul ScherrerInstitute, CH-5232 Villigen PSI, Switzerland a Université de Genè ve,Dé partementdeChimie Physique 30, quai Ernest-Ansermet, CH-1211 Genè ve 4, Switzerland Themolecular structureofNi/ -Al O catalystusedduring methanation of 2 3 b Institute of Physical and Theoretical Chemistry,WroclawUniversityof synthesis gaswas investigated using DFTmethod with anon-local func- Technologym, Wyb. Wyspiań skiego 27, 50-370 Wrocl aw,Poland tional [1]. Theseveral Ni-compounds such as Ni, NiO and Ni3 Caswellas -Al 2 O 3 surfaces wereconsidered. Furthermore,the geometricand theelec- The equilibrium geometries of the noncovalently bound molecular complexes tronic structures of Ni deposited on -Al 2 O 3 system were studiedindetails. have been obtained using subsystem formulation of densityfunctional[1] the- Thetheoretical studies arepresently used to help with understanding more ory applying proposed efficientoptimization algorithm. The representativeset detailedsurface modifications duringmethanation and reasons of anickel of molecules is chosen and divided into hydrogen-, dipole- and weakly-bounded particles detachment together withacarbon whiskersformation in specific spices as proposed by Truhlar[2] for acomparisions standart, where accurate fixed bed conditions.TheNi/ -Al 2 O 3 catalystindifferent stateofmethana- ab-initio benchmark data are available. We have also tested performance tion consists of several Ni-compounds such as Ni, NiO and Ni3 C, which was of two differentwaysofapproximating the exchange-correlation- and non- suggestedbyprevious experimental studies [2,3]. Our findings about elec- additivekinetic energy parts of total energy.The non-empirical local density tronic structuresuggestthat the nickel carbide is supposed to be less reac- approximation (LDA) leads to excellentequilibrium geometries and interac- tivethenpurenickel or nickel oxide. Thenickel adsorbsatAl 2 O 3 (100) sur- tion energies with accordance to reference data in all of the studied three sets. face in the hole position between surface oxygen centers. Thenickel deposi- The best results are obtained for the set of hydrogen bonded complexes where tion influences electronic properties of the Al2 O 3 surface by modificationof the maximal error in distance between subsystems reach0.13 Af˚ or NH3 - both oxygen andaluminum centers. TheNidopeselectrons to the system, NH3 [3]. The applicabilityofthe chosen generalized gradientapproximation whichleads to increaseofanegativecharge of oxygen centers. Thevisible is limited to cases where LDAfails, whichcompromises molecules involving asymmetryinNideposition at Al2 O 3 (100) surface suggeststhat the Ni π - π stacking suchasbenzene dimer, whichisalso confirmed by our previous would prefer localization at AlO4 tetrahedrons. studies[4].

[1] P. Cortona, Phys. Rev., 1991, 44,8454. [1]I.Czekaj,J.Wambach, A. Wokaun, Annual Report, Electrochemistry [2] D. G. Truhlar, Y. Zhao, J. Chem. Theory Comput., 2005, 1 ,415. LaboratoryPSI 2006,12. [3] M. Dulak, J. W. Kami´n ski, T. A. Wesolowski, J. Chem. Theory [2]I.Czekaj, F. Raimondi, J. Wambach, A. Wokaun, Annual Report, Elec- Comput.,inpress, trochemistryLaboratoryPSI 2005, 42. [4] T.A .Wesolowski,F.Tran, J. Chem. Phys., 2003, 5 ,2072. [3]F.Raimondi, M. Seemann,S.Biollaz, J. Wambach, A. Wokaun , PSI Scientific Reports 2003, 5, 116.

Computational Chemistry 91 Computational Chemistry 92

Elucidation of themechanismofhydrolysis by fatty acid amide TheConceptofProtobranching andits DFTTreatments hydrolase(FAAH) from QM/MM simulations MatthewD.Wodrich,a Clémence Corminboeuf, a,b P. v. R. Schleyer a Ivan Tubert-Brohman, Orlando Acevedo, WilliamL.Jorgensen* a Department of Chemistryand Center for ComputationalChemistry, Uni- University of Basel, Klingelbergstrasse 80, CH-4056 Basel, Switzerland. versity of Georgia,Athens,Georgia, USA 30602 AuburnUniversity; * Yale University. b Institute of Chemical Sciences andEngineering,Ecole Polytechnique FédéraledeLausanne, CH-1015 Lausanne, Switzerland FAAH is aserinehydrolase and apotential therapeutic target forsome neu- rological disorders. It is remarkable forhydrolyzing amides andesterswith Branched alkanes like isobutane and neopentaneare morestable than their similarrates;however, the normalpreferencefor esters reemergeswhen straight chain isomers, n -butane and n -pentane (by8.6 and 21.1 kJ/mol,re- Lys142 is mutated to alanine. To elucidate the hydrolysis mechanisms and spectively) due to the greater numberofstabilizing1,3-interactions.There the causesbehind this variation of selectivity, QM/MMcalculations using arethree 1,3-interactions in isobutanebut only twoin n -butane. We call Monte Carlosimulations and freeenergy perturbation theorywerecarried such attractive 1,3-interactions "protobranching" [1]. Protobranching also out to obtain free-energy profiles forvarious mechanisms forthe formation stabilizes all n -alkanes relative to ethane (which has none).Thereisone in of the acylintermediatefrom the Michaelis complex, using oleamide as the propane, two in n -butane, etc. Accuratecomputational treatmentsofproto- substrate. For wild-type FAAH, the results supportatwo-step mechanism, branchingare essential when assessing the energiesofphysical organic con- A ,which involves activation of the nucleophile by indirect proton abstrac- cepts. tion by Lys142 via Ser 217. For the mutant, astrikingconcerted mechanism, B, is proposed. Supportcomes fromthe free-energy results,which well re- produce the observation that the Lys142Ala mutation in FAAH decreases the rate of hydrolysis foroleamide significantly more than formethyl oleate.

Lys Lys Lys 142 142 142 + N N N H H H H H H H H H H H Ser O Ser O A Ser 217 217 N 217 O H N H H H H H R N H O O R O R O Ser Ser Ser 241 241 241 1a O 2b O 3a While correlated methods such as CCSD(T) do account forthis stabiliza- H H H H Ser 217 O tion, DFTmethods systematically underestimate protobranching interactions Ser N 217 O H N H H B R for n -alkanes,branched alkanes,and saturated hydrocarbon cages [2]. H O O R Ser O 241 Ser [1]M.Wodrich, P.v.R. Schleyer et al.submittedto Chem. Eur. J. 241 1a 3a O [2]M.Wodrich,C.Corminboeuf,P.v.R.Schleyer Org. Lett. 2006, 8 ,3631.

2006 COMPUTATIONAL CHEMISTRY440 CHIMIA 2007, 61,No. 7/8

Computational Chemistry 93 Computational Chemistry 94

Rebinding MolecularDynamicsSimulations of Nitric Oxidetothe An efficientdual-topology scheme for free-energy calculations V68FMyoglobin Mutant Teodoro Laino ,Guillaume Lamoureux† ,Juerg Hutter StefkaTsintsarska ,Markus Meuwly Physikalische Chemische Institut, ZürichUniversity, Winterthurerstrasse Department of Chemistry,University of Basel 190, 8057 Zürich Klingelbergstrasse 80, 4056 Basel, Switzerland † Center for Molecular Modeling, DepartmentofChemistry,Universityof Pennsylvania, Philadelphia, PA 19104-6323 USA Thestudy and modelling of reactive processesinchemically and biologically relevant systemshas been always an interesting scientific topic.Here, Free energy perturbation simulations playavital role in understanding chem- an atomistically detailed pictureofNOrebindingfrommyoglobin V68F is ical processes that occur in the condensed phase because they deal with ther- presented. Using reactive molecular dynamics[1] the rebinding probability modynamic quantities whichare independentofthe time scale of the studied as afunction of time after dissociation is calculated. Reactive molecular dy- processes. namicsconsiders two intersecting potentialenergymanifolds whichdissoci- Of particular interests are the so called alchemical free energy simulations atetodifferent adiabatic states.Duringthe simulations,crossings arede- in whichone chemical species is transformed reversibly into another using a tected by monitoringanenergy criterionand the surfaces aremixed over a coupling parameter λ .Relying on the fact that free energy differences are finite number of time steps.The unboundsurface (Fe...NO) is astandard independentofthe coupling path, manymethodological approaches have been forcefield, whereas the bound surface (Fe-NO) is based on ab initio calcula- proposed to solvethis problem[1]. All of them makeassumptions on specific tions.The rebinding is nonexponential in time,inagreement with experi- kind of Hamiltonians making the scheme itself not general and often difficult mental studies[2] andcan be describedusing two time constants.Particular emphasis is paid to the asymptotic separation between the two potential to be exported to other kind of problems. energy manifolds.Anextension of the original reactive molecular dynamics In this work we propose acombination of the standard dual-topology-dual- approach with aconformationally varying isdiscussed and implemented. coordinate technique[2] with an umbrella potential[3] in order to compute free Theadvantages and theresults of theconformationally dependant and con- energy differences. Since no assumptions have been made about the nature formationally independent -functionimplementations areanalized and of the two Hamiltonians, the methodshows ageneral applicabilitygoing from compared. classical molecular mechanics simulations up to fully ab initio simulations. The presence of the umbrella potential fixes the problems of the statistical sampling at the critical pointof λ =0and λ =1.The methodhas been implemented as amodule of the CP2K[4] suite of packages and applications will be shown in the field of ab initio simulations. [1]D.R.Nutt and M. Meuwly, Biophys.J. 2006, 90,1191. [1] A.Pohorille, C.Chipot (Eds.),Free Energy Calculations, 2007 [2]Y.Wang, J.S. Baskin, T. Xia and A.H. Zewail, Proc. Nat. Acad. Sci. USA 2004, 101, 52, 18000. [2] S.Boresch, M.Karplus,J. Phys. Chem. A , 1999, 103,103-118 [3] G.M.Torrie, J.P.Valleau,J. Comp. Phys., 1977, 23,187-199 [4] http://cp2k.berlios.de

Computational Chemistry 95 Computational Chemistry 96

Ab initio molecular dynamics simulation of liquid water Structural AssignmentofSpectra by Characterization of Conformational Substates in MbCO. I-Chun Lin1 ,Ari P. Seitsonen2 ,Ivano Tavernelli1 , Maur´ı cio D. Coutinho-Neto3 ,and Ursula Rothlisberger1 M. Devereux ,M.Meuwly

1 LCBC EPFL, Lausanne, Switzerland DepartmentofChemistry,UniversityofBasel, Klingelbergstrasse 80, 2 IMPMC CNRS Université Pierre et Marie Curie, Paris, France CH-4056, Basel, Switzerland 3 Centro de Ciê ncias Naturais eHumanas, Universidade Federal do Residue motions of the distal heme pocketofthe oxygen-storing protein Myo- ABC, São Paulo, Brazil globin have been shown to influence protein function, control ligand rebinding rates [1], and have been implicated in ligand recognition [2]. Forcarbon- The ubiquityofwater invariably leads to its importantroles in most bi- monoxy Myoglobin (MbCO) both the ligand bound (MbCO, A-state) and ological, chemical and environmental processes. Yet, despite extensive unbound (MbCO, B-state) have been characterized by x-raycrystallography. studies, its microscopic nature, whichcould be of help in understanding Because ligand binding and unbinding are transientprocesses in nature, it is these processes, remains elusive. Precise knowledge of the intermolec- difficult to experimentally characterize both structural and dynamic properties ular interactions in water will faciliate abetter understandingofthis of the system. Atomistic simulations using validated force fields provide addi- ubiquitious substance. tional insight[3,4]. In further studies [2,5], Molecular Dynamics simulations Here, we employedCar-Parrinello molecular dynamics with DFT-BLYP have linked theoretical motions of residues within the heme pockettochanges to probethe structural and dynamical properties of water. The poorde- in observed spectroscopicA-states. The distinct A-states of the bound CO scription of weak interactions in DFT-BLYP,whichmay be one of the ligand were attributed to differentorientations and protonation states of the possible causes for the overstructuring observed in DFT-BLYP water, is adjacentHIS64 moiety. Here we characterize the bound states A0, A1 and remedied using dispersion corrected atom centered potentials [1]. Prop- A3 using acombination of molecular dynamics simulations and DensityFunc- erties suchasradial distribution functions, mean square displacements, tional Theory calculations. Calculated absorption bands were derived from molecular dipole moments, and hydrogen bond statistics will be pre- differentconfigurations for comparison with experimental results. The experi- sented. mentaldataisthenusedtoguide refinementofthe original CHARMM model. Particular attention is paid to the charge model of the bound CO ligand, key [1] O. A. vonLilienfeld et al., Phys. Rev. Lett., 2004, 93,153004. to representing interaction with the local binding site. [1] S. Kim, M. Kim, J. Am.Chem. Soc., 2005, 127,8909. [2] A. Loccisano, O. Acevedo, et al., J. Mol. Graph. Model., 2004, 22,369. [3] D. Nutt, M. Meuwly, PNAS, 2004, 101,5998. [4] M. Meuwly, Chem. Phys. Chem., 2006, 7 ,2061. [5] C. Rovira, B. Schulze et al., Biophys. J., 2001, 81,435. COMPUTATIONAL CHEMISTRY441 CHIMIA 2007, 61,No. 7/8

Computational Chemistry 97 Computational Chemistry 98

Ab Initio Surface-Hopping DynamicsofEthyl Radical Ab-initio dynamics of the adsorption and reactivityofketones on Pt(111) JonasM.Hostettler ,Andreas Bach, PeterChen Angelo Vargas,Gianluca Santarossa and Alfons Baiker ETH Zürich,Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland Institute for Chemical and Bioengineering DepartmentofChemistry and Applied Biosciences, ETH Zurich, Ethyl radical is an important intermediate in hydrocarbon crackersand com- Honggerberg, HCI, 8093 Zurich bustion processes, playing acentral role as the principalprecursortoethyl- ene through lossofahydrogen atom. Tworecent studies1,2 of thedissocia- Heterogeneous catalysis occurs at the interface between asurface and tion dynamics of ethyl have found that highly excitedradicals can dissociate with afastand aslowcomponent, with the slower component decaying four agas or aliquid, and very often the mechanisms at the base of such to five orders of magnitude moreslowly than predicted by Rice chemical transformations are not known. Experimental techniques for RamspergerKasselMarcus RRKMtheory, even though the 5-eV excita- the analysis of surface phenomena exist but often fail to yield critical de- tionenergy farexceeds the1.6-eVbarrier to dissociation. tails of the reaction pathway.One very importantclass of heterogeneous reactions for whichdetailed mechanistic insightisnot available are hydro- genations on transition metals, broadly used in both industrial and fine chemical synthesis. In this contribution an ab-initio molecular dynamics study of the adsorption and reactivityofdifferently substituted ketones is h C.I. presented, whichaims at clarifying surface reaction intermediates, transition states of the reaction, together with the effect of α -substitution on reaction parameters.

Theanomalous and unexpected kinetic behaviour is investigated by on-the- flyCASSCFnonadiabatic dynamics 3 to model thefastdecay of the first excited state through aconical intersection. Thesimulations result in an ex- citedstate lifetime of 27 fs,bimodalproduct energy distributions and show no isotopic scrambling of the reaction products.Theseresults stand in good agreement with experimentalfindings. 1,2 Further simulations apply MRCI values to incorporate effects of dynamical correlation. [1] A. Vargas, T. B¨urgi, A. Baiker, J. Catal., 2004, 222,439. [1] Gilbert,T.; Grebner, T. L.;Chen, P. J. Chem. Phys. 1999, 110, 5485. [2] E.L. Jeﬀery, R.K. Mann, G.J. Hutchings, S.H. Taylor, D. [2]Amaral, G.;Xu, K. S.;Zhang, J. S. J. Chem. Phys. 2001, 114,5164. Willock Catal. Today, 2005, 105,85. [3]Tully, J.C. J. Chem. Phys. 1990, 93,1061.

Computational Chemistry 99 Computational Chemistry 100

Solid-Solid PhaseTransitions: Theoretical investigation of infrared spectra and pocketDynamics Nanointerface Reactivityand FormationofMetastablePhases of Photodissociated Cabonmonoxy Neuroglobin

Stefano Leoni Stephan Lutz,Markus Meuwly

Max-Planck-Institut für ChemischePhysik fester Stoffe, DepartmentofChemistry,UniversityofBasel, CH-4056 Basel, Switzerland Nöthnitzer Str.40, 01187 Dresden, Germany, [email protected] Neuroglobin (Ngb) is asmall globular protein, expressed in the brain of man and mouse. whichcan bind ligands suchasoxygen, carbon monoxide (CO) Findingnew pathwaystonovel materials is an open challenge in modern and nitric oxide at aheme prostetic group. The X-raystructure, whichwas solid statechemistry. Metastablephases areinthisrespect apowerfulpoint solved in 2003 [1], shows some particular features whichdistinguish Ngb from of access to new materials.Thus apreciseatomistic understanding of the other members of the globin family [2]: The proximal histidin (His-96) can reactivity in the solid state, in its many facets(critical processeswith phase bind to the heme-iron atomintwo conformations and the heme group ap- coexistence, reactivity of interfaces,nucleationpatterns),ismandatory. Re- pears to be considerably more mobile. Spectroscopically,carbonmonoxide as cently we have started asystematic theoretical study of phasetransitions aligand wascharacterized in its unbound (Ngb ··· CO) state using IR spec- with firstorder thermodynamics [1-3]toreach afirmunderstanding of the troscopy[3]. Using molecular dynamics and afluctuating charge model for CO atomisticmechanismsbehind polymorphisminsolid state. Aclear pictureis [4] the infrared spectrum wascalculated. Twodifferentdocking sites within emerging of the interplay between nucleation patterns,domain interface the activesite of Ngb were found whichconfirms results from FTIR experi- reactivity and final materialmorphology [4]. Therein intermediate metasta- ments. Barriers for the migration between these two pockets were calculated ble phaseswith distinctatomic patterns areidentified. CdSe,CaF2 and AgI and compared to results from TDS measurements. Furthermore, the simu- arethree different examples of reactivity governedbynanointerfaces.We lations confirm the experimental observation for the higher flexibilityofthe have investigated CdSe in aset of simulations andexperiments [5,6]. TEM heme plane compared to other globins suchasmyoglobin and giveinsightinto experiments combinedwith computersimulations unfold the composite na- its dynamical behaviour after CO dissociation. ture of the materialafter application of pressure.Low dimensionalnanosur- faces formed under pressure areresponsible forthe recrystallization of the [1] Pesce, A., Dewilde, S., Nardini, M., Moens, L., Ascenzi, P.,Han- keln, T., Burmester, T., and Bolognesi, M., Structure , 2003, 11, fluoride sublatticeinCaF2 [6]. Metastablephases areformedatinterfaces in AgI during pressure or temperatureinduced phase transitions [6]. Therein 1087. stacking disorder enhances the mobility of silverions. [2] Vallone, B, Nienhaus, K., Matthes, A., Brunori, M., and Nienhaus, G.U., PNAS, 2004, 101,17351. [1]S.Leoni,Chemistry. AEuropean Journal, in press . [3] Nienhaus, K., and Nienhaus, G.U., Journal of Biological Physics, [2]D.Zahn, S.Leoni, PRL 92 (2004),250201. 2005, 31,417. [3]S.Leoni,D.Zahn, Z. Kristallogr. 219 (2004), 339. [4] Nutt, D.R., Meuwly,M., Biophysical Journal, 2003, 85,3612. [4]D.Zahn, O. Hochrein,S.Leoni,PRB 72 (2005), 94106. [5]D.Zahn, Yu.Grin, S. Leoni,PRB 72 (2005), 64110. [6]S.Leoni, in preparation. COMPUTATIONAL CHEMISTRY442 CHIMIA 2007, 61,No. 7/8

Computational Chemistry 101 Computational Chemistry 102

LFDFTcalculationsofZeeman andzero-fieldsplitting tensors MicrosolvationEffectsonthe Excited-StateDynamicsof forhigh-spin transitionmetal complexes Protonated Tryptophan

Alain Borel SebastienR.Mercier, OlegV.Boyarkin, Anthi Kamariotis, MatteoGuglielmi, Ivano Tavernelli,Michele Cascella, Institut dessciences et ingénieriechimiques, Ecole Polytechnique Fédérale Ursula Rothlisberger, and Thomas R. Rizzo de Lausanne, EPFL-SB-ISIC-GE, CH-1015 Lausanne (Switzerland) Ecole Polytechnique Federale de Lausanne LFDFT has been proposed over the pastfew yearsasasystematic method CH-1015 Lausanne, Switzerland forthe study of ground and excited multipletstatesoftransition metal compounds,wherethe ligand-field approach is reformulated within the frame- workofdensity-functional theory. Themethodallows the determination of To better understand the complex photophysicsofthe amino acid trypto- all d-d[1] or f-f[2] excitation energies foragivensystem, and was used to phan,which is widelyusedasaprobe of protein structureand dynamics,we calculate the magnetic propertiesoflow-spinmolecules[3]. This work ex- have measured electronicspectra of protonated,gas-phasetryptophan sol- tends the lattermethod to the caseofhigh-spin complexes. vated with acontrollednumberofwater moleculesand cooled to ~10 K. We observe that,even at this temperature, thebaremoleculeexhibits abroad electronicspectrum, implyingultrafast,nonradiativedecay of theexcited state. Surprisingly, the addition of two watermoleculessufficiently length- ensthe excited-state lifetime thatweobtain afully vibrationally resolved electronicspectrum. Quantum chemical calculations at theRI-CC2/aug-cc- pVDZ level, togetherwith TDDFT/pw basedfirst-principles MD simulations of the excited-state dynamics, clearly demonstrate how interactions with water destabilize the photodissociative states and increasethe excited- statelifetime. By showing how one can relate the LFDFT andeffective spin Hamiltonians forsuch systems,ameaningful comparison with experimental data or other theoretical methods becomes possible, as demonstrated forafewselected examples.

[1]M.Atanasov, C. A. Daul and C. Rauzy, Struct. Bond. 2004, 106,97. [2] L. Petit et al., Inorg. Chem. 2006, 45,7382. [3]M.Atanasov et al., Chem. Phys.Lett., 2004, 399 ,433. Laboratoire de Chimie Physique Moleculaire. Laboratoire de Chimie et BiochimieComputationelle.

Computational Chemistry 103 Computational Chemistry 104

Virtual Exploration of Chemical Space by DFTModeling of HNCO Hydrolysis over theTiO2 (101)Surface Guided Travelbetween Reference Structures IzabelaCzekaj,Oliver Kröcher,GaiaPiazzesi Ruud vanDeursen and Jean-Louis Reymond Paul ScherrerInstitute, CH-5232 Villigen PSI, Switzerland UniversityofBerne, Freiestrasse 3, CH-3012 Berne, Switzerland DecreasingNO emission limits for dieselenginesimpelthe further The chemical space of organic structures up to aMW-range of 500 Da x development of existing DeNOx technologies,particularly the selective is of particular interest for new structures with therapeutic applications. catalytic reduction of nitrogen oxides with urea (urea-SCR).Inthisprocess In previous work chemical space belowMWof160 Da wasexhaustively aureasolution is injected into the exhaustgas andthermolyzed to ammonia listed with atotal number of more than 26 Mio. possible structures, and isocyanic acid (HNCO),which is further hydrolyzed to ammonia and showing howvast chemical space can be [1]. We herewith present Chem- carbon dioxide. This reaction was found to be catalyzed by TiO 2 in the ana- ical SpaceTravel as anew type structure generator to explore chem- tasemodification, which is,therefore, used as hydrolysis catalyst in the ical space beyond MW of 160 Da. The program travels from astart urea-SCRprocess. Themechanismofthe hydrolysis of isocyanic acid to atarget molecule that both are proventobetherapeutically active (HNCO) was studied on the ideal TiO 2 anatase(101) surface using the ab- and therefore deﬁne favourable regions in chemical space for the chosen initio d ensity f unctional t heory(DFT) method with acluster model. Based target. Chemical Space Travelcombines structural pointmutations as on the energy levels of different possible transitionstatesand intermediates propulsion device and aselection module that holds trackonthe target two mechanistic pathways have been identifiedtobefeasible for this by measuring similarity[2]. The principle is demonstrated and analysed reaction. In one mechanismHNCOismolecularily adsorbedand an inter- by travelling from methane, the smallest structure in the organic chemi- mediatesurface complex is formed by NCO skeleton modification[1]. cal space, to diﬀerenttargets and by travelling between two structures. Whereas waterisabsentatthe beginning of reaction in this mechanism, water is included at an early stage in the second scenario [2]. In this [1] T. Fink and J.-L. Reymond, Angew. Chem. Int. Ed., 2005, pathwayawater molecule attacksthe NCOgroup, thereby forming 44,p.1504-1508; T. Fink and J.-L. Reymond, J. Chem. Inf. carbamic acidatthe surface. In afurther step this compound is transformed Model., 2007, 47,p.342-353. to acarbamate complex, from whichCO 2 desorbsand NH3 is finally [2] R. vanDeursen and J.-L. Reymond, ChemMedChem, 2007, formed. in press.

[1]I.Czekaj,G.Piazzesi, O. Kröcher,A.Wokaun, Surf. Sci. 600 (2006) 5158. [2]I.Czekaj,O.Kröcher,G.Piazzesi, in preparation. COMPUTATIONAL CHEMISTRY443 CHIMIA 2007, 61,No. 7/8

Computational Chemistry 105 Computational Chemistry 106

Photoinduced ring opening of oxirane: anon-adiabatic Development of Hybrid-Quantum ChemicalMethods for Modeling molecular dynamics study Ligand-ProteinInteractions

Enrico Tapavicza,Ivano Tavernelli, Ursula Roethlisberger Celine Amoreiraand Kim K. Baldridge, Celine Amoreira

Ecole Polytechnique Fédé rale de Lausanne Department of Organic Chemistry University of Zürich The modeling of non-adiabatic excited state reactions constitute one of 190 Winterthurerstrasse the major challenges of modern computational chemistry.Time-dependent Zürich, CH-8057 Switzerland densityfunctional theory (TDDFT) [1] in the linear response (LR) for- [email protected] mulation [2] allows the computation of electronic spectra, excited state nuclear forces [3] and non-adiabatic couplings [4,5,6]. Theory and im- Quantum chemical methodsenablecalculationofchemical reactions using plementation of asurface hopping molecular dynamics [7] scheme using highlyaccuratealgorithms.Despite advances,however,itremains difficult LR-TDDFT [6] is presented. The scheme is applied to study photoin- to modelcomplexsystems such as biomolecules. In this work, we investi- duced ring-opening of oxirane. gate the possibilities of ahybrid quantum mechanics and adaptive Poisson- Boltzmann (GAMESS[1] /APBS[2] )method forinvestigationsinvolving [1] E. Runge, E.K.U. Gross, Phys.Rev.Lett., 1984, 52,997. ligand-protein interactions.The results have been in part obtained using [2] M.E. Casida, in Recent Advances in Density Functional Meth- modern grid computing. Thealgorithm involves theembedding of the field ods ,edited by D. P. Chong (Singapore, World Scientific, 1995), generated by the APBSmethod into the quantum mechanical Hamiltonian p. 155. operator,and the resulting self-consistent field computation on the complex [3] J. Hutter, J.Chem.Phys., 2003, 118,3928. of interest.The algorithm will be demonstratedonakeyligand-protein sys- [4] R. Baer, Chem.Phys.Lett., 2002, 364,75. temofinterest. [5] N.L. Doltsinis, D.S. Kosov, J.Chem.Phys., 2005, 122,166402. [6] E. Tapavicza, I. Tavernelli, U. Rothlisberger, Phys.Rev.Lett., This workissupported by agrant fromthe SwissNational Science Founda- 2007, 98,023001. tion(SNF). [7] J.C. Tully, J.Chem.Phys., 1990, 93,1061.

[1]Schmidt, M.W.,etal., General Atomic and Molecular Electronic- StructureSystem. Journal of Computational Chemistry, 1993.14(11):p. 1347-1363 [2]Baker,N.A., et al., Electrostatics of nanosystems:Application to micro- tubules and the ribosome. Proceedings of theNational AcademyofSci- ences of the United States of America, 2001. 98(18):p.10037-10041.

Computational Chemistry 107 ComputationalChemistry 108

Farmingfor a5-HT 2A Pharmacophore. Core Electron SpectroscopyofGlycine and Glycine-Based Polypeptides in Aqueous Solution Anne Dara Bowen ,Kim Baldridge* Samuele Giani a ,Jü rg Hutter a ,Marcella Iannuzzi b University of Zurich,Winterthurerstrasse 190. 8057Zurich, Switzerland a Physikalisch-Chemisches Institut, Universität Zürich, Winterthurerstr. 190, CH-8057 Zürich b Paul Scherrer Institut, CH-5232 Villigen PSI

The5-HT 2A receptor is thetargetofmanyatypical antipsychotic drugs used to treat psychological conditions such as schizophrenia. The Recently,anapproachfor calculating X-rayabsorption spectra based exact mechanism by which thethisreceptor mediates theactionofthisclass on the transition potential methodcombined with the Gaussian and of drugs is unknown. Thereisnoexperimental data forthe 3D structureof augmented-plane wave method(GAPW) has been introduced [1]. For this particular receptor subtype, and many attemptsatderiving aquantitative this type of spectroscopy, the promotion of acore electron to an unoccu- structureactivity model of drugs that interact with this receptor arebased on pied orbital and the resulting relaxation of the electronic structure has binding anumber of ligands to ahomology modelofthe receptor.The ap- to be appropriately modeled. The GAPW formalism allows for eﬃcient proach presentedherefocuses instead on identifying and testing quantum DFT all-electron calculations of extended systems, making this frame- mechanical descriptors that seem to be predictive of binding specificity and work appealing for condensed phase X-rayspectroscopy. affinity as wellasbiological activity.Particular emphasis is placed on properties(such as the sigma profile andthe partition coefficient)thatcan We focus on excitation spectra of glycine and glycine-based oligomers in be calculatedfrom GAMESS-COSab quantum mechanical implementation aqueous solution. The calculations were performed along classical MD of adielectric continuum solvation model .Thesefindings areusedtopre- trajectories and compared with reported experimental spectra [2]. The sent aquantum mechanically basedpharmacophoremodel forthe mecha- analysis of conformation–dependentsignal patterns of absorption leads nism of antipsycotic drugs acting at the 5-HT receptor.Inorder to better 2A to the interpretation of the transitions in thermsofthe dynamicalre- understand the pharmacophoreand validate thedata, the same setofmole- orientation of hydrogen bonds between donor–acceptor partners. This cules is also tested usingacommercialy availableQSARsoftwarepackage. technique opens new perspectives towards the characterization of the Theresults of the QSARtestand the quantum mechanically based pharma- nature of the H–bonds, clarifying howthe number and the strength of core modelare used to outline aschemaand interface for for ahigh- throughput methodology forscreening drugs that actatthis receptor. the local coordination sphere aﬀects the spectra. [1] M. Iannuzzi, J. Hutter, Phys. Chem. Chem. Phys., 2007, 9 , 1599. [1]Schulze-AlexandruM,Kovar K, Vedani A, QSAR. 1999, 18,548-560. [2] B.M.Messer, C.D. Cappa, J.D. Smith, W.S. Drisdell, C.P. [2]Glen R, AdamsS, QSARComb. Sci. 2006, 12,1133-1142. [3]KarelsonM,Lobanov V, Chem. Rev. 1996, 3 ,1027-1044. Schwartz, R.C. Cohen, R.J. Saykally, J. Phys. Chem. B , 2005, 109,21640. COMPUTATIONAL CHEMISTRY444 CHIMIA 2007, 61,No. 7/8

Computational Chemistry 109 Computational Chemistry 110 Expanding thesmall-molecule GDBwithfocused libraries of ligands for Multiway PLScalibration modelbased on Molecular Lipophilicity ionotropicglutamate receptors Potentialand GRID MolecularInteractionFields with artificialmembranePAMPA-skinexperimentaldata Kong Thong Nguyen,Jean-Louis Reymond*

1,2 1 1 2 1 Department of Chemistryand Biochemistry, University of Berne, J. Boccard ,G.Ottaviani ,S.Martel ,S.Rudaz ,P.A.Carrupt Freiestrasse 3, CH-3012 Berne, Switzerland 1 LCT-Pharmacochemistry We have recently reportedthe so-calledGenerated Database(GDB) [1] 2 LaboratoryofPharmaceutical Analytical Chemistry consists of 26.4millions smallorganic moleculesupto11C,N,O,Fatoms. School of Pharmaceutical Sciences,EPGL, 30, quaiErnest-Ansermet This database is an abundant source of numerous synthetically feasible small-molecule ligands for various drug targets.Hereinwereport the further 1211 Geneva 4, Switzerland,University of Geneva, University of Lausanne. expanding of the GDB databasewith thegenerated focused-librariesofas- partic acid and glutamic acidsanalogs targetingthe human ionotropic glu- Multiwaycalibration methods (such as PARAFAC,Tucker and N- tamate receptors.Advanced molecular modelingand chemoinformatic PLS) have been shown to be powerfultoolstoextract relevant chemical methods werealsoimplemented to predict the bioactivity and to analyze the information from MolecularInteractions Fields (MIF) in the context of structure-activity relationships among compounds in thosefocused libraries CoMFA[1]. AmultiwayN-PLS modelwas proposed to investigate artifi- in silico .The hit-listfromvirtual screening of the generated focused libraries offers aset of drug-like new structures which areveryinteresting in term cial membrane PAMPA-skinexperimentaldata[2] from aset of 53 com- of synthesis. pounds and their permeation profiles evaluatedby3Ddescriptorsbased on GRID probes and MolecularLipophilicity Potential (MLP)[3].Low energy conformation wascalculated foreach compound and molecules were [1] T. Fink, J.L.Reymond, J. Chem. Info.Model. 2007, 47,342; T. Fink, aligned in the same coordinate system using conventionalalignment meth- H. Bruggesser, J.L.Reymond, Angew. Chem. Int. Ed. 2005, 44,1504. ods.Molecular Interactions Fields were generated using an in-houseMLP routine andGRIDsoftware with commonly-used probes. Multiwaypre- treatment andcalibration were performedwith Matlaband aN-PLSmodel was calibrated on the 5D hypercube (molecules *MIF *X*Y*Z). The finalmodelwas validatedusing Leave-One-Out crossvalidation. This study showedthatmultilinear N-PLSmodelling is asuitable tool for the evalua- tion and the comparison of MIFdescriptors as it provided valuable information to bettercharacterize the structural properties of the compounds.

[1]J.Nilsson, S. De Jong, A.K. Smilde, J. Chemom. 1997,11, 511. [2]G.Ottaviani, S. Martel, P.A.Carrupt, J. Med. Chem. 2007,50, 742. [3]P.Gaillard, P.A. Carrupt,B.Testa,A.Boudon, J. Comput.-Aided Mol. Design 1994,8,83.

Computational Chemistry 111 Computational Chemistry 112

ApplicationofaQuantumMechanical solvationmethodfor theoretical On the DFT calculation of the adsorptionenergy of benzene Corannulene studies on Pt(111)

Yohann Potier,Kim Baldridge* Gianluca Santarossa,Angelo Vargas, Alfons Baiker

University of Zürich,Winterthurerstr.190, CH-8057Zürich, Switzerland Institute for Chemical and Bioengineering DepartmentofChemistry and Applied Biosciences In the development and refinement of continuumsolvationmodels,highly ETH Zurich, H¨onggerberg, HCI, 8093 Zurich, Switzerland accurate continuum-dielectric models that candescribesubtle effects in structureand reactivity processesare adesirable endpoint. Detailed chemi- The heat of adsorption of benzene on Pt(111) has been extensively stud- caltreatmentsofmolecular and electronicstructure with theinclusion of the ied by means of temperature programmed desorption (TPD) [1], single effectsofthe environment enabletopredict molecular geometry,follow crystal adsorption calorimetry (SACS) [2] and densityfunctional theory reactionpaths,predict electrostatic effectsinavariety of environmentswith calculations (DFT) [3]. RecentSACSexperiments showadsorption en- an accuracy not offeredbygas phaseanalysis [1]. ergies almost twice as large as the ones previously published, and also Still, there areseveral areas of application where even refineddielectric in large disagreementwith DFT calculations [2]. In order to understand modelshavedifficulty in establishing reliable predictability. Solvation the origin of this disagreementadetailed DFT study of the adsorption modeling is particularly challenging forionicspecies,due to strong electro- of benzene on Pt(111) surfaces is performed, using both cluster models static effects arising fromunbalanced localizedcharges.Aswell, dynamical and periodic boundary conditions to model the metal. processes, which change as afunction of either solvent volume or solvent dielectricand/or change mechanistically acrosssmall ranges in dielectric, alsorepresent achallenge forcontinuum models. In this study, we show results fromour generalquantum mechanic solvation algorithm forthe prediction pKa constants,and formodeling the dynamics of polynucleararomatic hydrocarbon systems,inparticular corannulene (C20H10) based structures [2], both applications in thesedifficult regimes.

[1]Gregerson, L.N.and K.K. Baldridge, HelveticaChimicaActa. 2003. [1] Campbell, J. M.; Seimanides, S.; Campbell, C. T. J. Phys. 86(12),4112 Chem. 1989, 93,815-826. [2]Seiders,T.J., K.K. Baldridge,and J.S. Siegel, Journal of the American [2] Ihm, H.; Ajo, H. M.; Gottfried, J. M.; Bera, P.;Campbell, C. Chemical Society. 2001 123 (4), 517 T. J. Phys. Chem. B 2004, 108,14627-14633. [3] Morin, C.; Simon, D.; Sautet, P. J. Phys. Chem. B. 2004 , 108,12084-12091. Bonalumi, N.; Vargas, A.; Ferri, D.; Baiker, A. J. Phys. Chem. B 2006, 110,9956-9965. COMPUTATIONAL CHEMISTRY/INORGANIC AND COORDINATION CHEMISTRY445 doi:10.2533/chimia.2007.445 CHIMIA 2007, 61,No. 7/8

Computational Chemistry 113 Computational Chemistry 114 ProgressonComputationofMolecularParityViolation Usingthe Ab Initio Study of Some Persistent Nitroxide Radicals Coupled-Cluster Linear ResponseApproach ubo Horn,Fabio Mariottiand Martin Quack ubo Horn,Martin Quack andMartin Willeke Physical Chemistry, ETHHönggerberg, CH-8093 Zürich, Switzerland Physical Chemistry, ETHHönggerberg, CH-8093 Zürich, Switzerland Stable freeradicals have avariety of applications.Particularly, the aminoxyl Progress hasbeen made in the theoretical description of molecular-parity group is frequently used in spin-labeling experiments.Nitroxides may also violation over thelastdecade1-4 ,and its possible implications forthe origin exhibit intriguing chiral andmagnetic properties andmustbeofinterestfor of molecularchirality andbiomolecularhomochirality, as well as possible studies of molecular parity violation1,2 .Three different groups of persistent 5-8 3-5 experiments on molecular parity violationare of fundamental interest . NO-radicals:i) acyclic :dimethylaminoxyl (Me 2 NO),bis(trifluoromethyl) 1,2 6-8 Following our previous work ,wereportnew developments to computa- aminoxyl (CF 3 ) 2 NO, and [(CMe 3 ) 2 NO]; ii) cyclic :aziridine-N-oxyl, tion of molecularparity-violation potentialEpv.Particularly,weseek foran azetidine-N-oxyl, pyrrolidine-N-oxyl and piperidine-N-oxyl; and iii) nitro- effectiveand controllableway to examinethe importance of electroncorre- nylnitroxides9 .Weuseddensity functional and ab initio (MP2, coupled lation forthe parity-violating potential.Since, thecoupled cluster method9 cluster)methods.The molecular structures,harmonic vibrational frequen- has proved to be amostrigorous approach to account forthe electron corre- cies,and inversion barriersare reportedand compared with experiment lation in molecules, we show how the linear response function10 of the cou- when available. Thecyclic species exhibitconsiderableinversion barriersof -1 -1 pled cluster wavefunction provides thecontributions to E pv.Wediscuss the ~hc 3500 cm compared to only ~hc 500 cm forthe acyclic ones.Nitronyl algorithms and computational steps,which arebeing developed, to achieve nitroxidesare theoretically characterized for the firsttime in our work. We the effective coding of this property.The results will be importantfor future discuss thepossibilitiesthatsomeofthe chiralderivativesmay be domi- accurateanalyses of experimental results7 . nated by molecular parity violation in their dynamics.

[1]A.Bakasov, T. K. Ha andM.Quack,J.Chem. Phys., 1998,109,7263. [1]M.Quack, Angew.Chem. Intl.Ed. (Engl.) 1989, 28, 571. [2]R.Bergerand M. Quack, J. Chem.Phys., 2000,112, 3148. [2]M.Quack, Angew.Chem. Intl.Ed. (Engl.) , 2002, 41, 4618. [3]R.Berger, In Relativistic Electronic StructureTheory, Vol. 2 , 2005,188. [3]P.W.Harland, Int. J. Mass Spect.&IonPhysics 1977, 25, 61. [4]M.Quack and J. Stohner,Chimia, 2005,59, 530. [4] C. Chatgillaloglu et al., J. Phys.Chem. 1980, 84,3597. [5]M.Quack, Angew.Chem. Intl.Ed. (Engl.) 1989, 28, 571. [5]D.A.C.Compton, C. Chatgillaloglu, H. H. Mantsch,K.U.Ingold, J. [6]M.Quack, Angew.Chem. Intl.Ed. (Engl.) , 2002, 41 4618. Phys.Chem. 1981, 85, 3093. [7]M.Quack, In Modelling Molecular Structureand Reactivity in Bio- [6]I.Komaromi, J. M. J. Tronchet, J. Phys.Chem. 1995, 99, 10213. logicalSystems,Proc. 7th WATOC Congress, Cape TownJanuary2005, [7]A.Ebrahimi et al., J. Mol. Struct.(THEOCHEM) 2001, 535, 247. 2006, 3(RoyalSociety of Chemistry,Cambridge). [8]I.Novaketal., J. Org. Chem., 2004, 69, 7628. [8]M.Quack, Chem. Phys.Lett., 1986, 132,147. [9]C.Hirel,J.Pecaut, S. Choua, Ph. Turek, D. B. Amabilino, J. Veciana, P. [9]J.Paldus,In Methods in Computational Physics , 1992,99. Rey, Eur. J. Org. Chem. 2005, 348. [10] O. Christiansen,P.Jørgensen,and C. Hättig, Int. J. Quant. Chem. 1998, 68, 1.

Inorganic and Coordination Chemistry 115 Inorganic and Coordination Chemistry 116

SmallMolecule Activationand Generation by EarlyTransition ChemistrywithAminylRadical Complexesand RelatedCompounds: Metal Complexes NewPerspectives forCatalysis

ChristopherC.Cummins Hansjörg Grützmacher

ChemistryDepartment,Massachusetts Institute of Technology, Laboratoriumfür Anorganische Chemie,ETH Hönggerberg, HCI Cambridge,MA02139-4307 (USA) CH-8093 Zürich,Switzerland