DOCSLIB.ORG

Atomistic Protein Folding Simulations on the Submillisecond Time Scale

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Atomistic Protein Folding Simulations on the Submillisecond Time Scale Vijay S. Pande1–4 Ian Baker1 Atomistic Protein Folding Jarrod Chapman4,* Sidney P. Elmer1 Simulations on the Siraj Khaliq5 Submillisecond Time Scale Stefan M. Larson2 Using Worldwide Distributed Young Min Rhee1 Michael R. Shirts1 Computing Christopher D. Snow2 Eric J. Sorin1 Bojan Zagrovic2 1 Department of Chemistry, 4 Stanford Synchrotron Stanford University, Radiation Laboratory, Stanford, CA 94305-5080 Stanford University, Stanford, CA 94305-5080 2 Biophysics Program, Stanford University, 5 Department of Computer Stanford, CA 94305-5080 Science, Stanford University, 3 Department of Structural Stanford, CA 94305-5080 Biology, Received 27 March 2002; Stanford University, accepted 22 May 2002 Stanford, CA 94305-5080 Abstract: Atomistic simulations of protein folding have the potential to be a great complement to experimental studies, but have been severely limited by the time scales accessible with current computer hardware and algorithms. By employing a worldwide distributed computing network of tens of thousands of PCs and algorithms designed to efficiently utilize this new many-processor, highly heterogeneous, loosely coupled distributed computing paradigm, we have been able to simulate hundreds of microseconds of atomistic molecular dynamics. This has allowed us to directly Correspondence to: Vijay S. Pande; email: pande@stanford. edu *Present address: Physics Department, University of California, Berkeley, CA Contact grant sponsor: ACS PRF, NSF MRSEC CPIMA, NIH BISTI, ARO, and Stanford University Contact grant numbers: 36028-AC4 (ACS PRF), DMR-9808677 (NSF MRSEC CPIMA), IP20 6M64782-01 (NIH BISTI), 41778- LS-RIP (ARO) Biopolymers, Vol. 68, 91–109 (2003) © 2002 Wiley Periodicals, Inc. 91 92 Pande et al. simulate the folding mechanism and to accurately predict the folding rate of several fast-folding proteins and polymers, including a nonbiological helix, polypeptide ␣-helices, a ␤-hairpin, and a three-helix bundle protein from the villin headpiece. Our results demonstrate that one can reach the time scales needed to simulate fast folding using distributed computing, and that potential sets used to describe interatomic interactions are sufficiently accurate to reach the folded state with exper- imentally validated rates, at least for small proteins. © 2002 Wiley Periodicals, Inc. Biopolymers 68: 91–109, 2003 Keywords: atomistic protein folding; microsecond time scale; computer hardware; computer algorithms; molecular dynamics; distributed computing; villin; beta hairpin INTRODUCTION Developing such large-scale parallelization meth- ods is very difficult, and current parallelization Understanding the sequence–structure relationship of schemes cannot scale to the level of even thousands of proteins will play a pivotal role in the postgenomic processors (i.e., cannot use so many processors effi- era, and will have great impact on genetics, biochem- ciently). To understand why scalability to thousands 1–3 istry, and pharmaceutical chemistry. A detailed of processors is so difficult, consider an analogy to a picture of the folding process itself will be important graduate student thesis. A typical thesis takes 1500 in understanding diseases, such as Alzheimer’s and graduate student days. If one employed 1500 graduate variant Creutzfeldt–Jacob disease, believed to be re- students to accomplish this goal, would it be possible 4 lated to protein misfolding. Finally, an understanding to complete a thesis in a single day? Clearly not—the of protein folding mechanisms will be important in overhead of communication between students, as well protein design and nanotechnology, in which self- as the inability to devise an “algorithm” to divide the assembling nanomachines may be designed using labor evenly, would make 100% efficiency impossible synthetic polymers with protein-like folding proper- 5 in this case. At this level of scaling, it is likely that the ties. work would actually take longer. These issues, in Unfortunately, current computational techniques to particular balancing communication time against time tackle protein folding simulations are fundamentally spent actually doing work, are mirrored in the division limited by the long time scales (from a simulation of labor between computer processors. Clearly, the point of view) needed to study the dynamics of inter- only way to efficiently utilize such a large number of est. For example, while the fastest proteins fold on the processors is to divide work in such a way that re- order of tens of microseconds, current single com- quires minimal communication. puter processors can only simulate on the order of a Even with an algorithm with perfect scalability nanosecond of real-time folding in full atomic detail per CPU day—a 10,000-fold-computational gap. (e.g., with a 10,000-fold increase in speed using Great strides in traditional parallel molecular dynam- 10,000 processors), we are still left with the problem ics (MD), utilizing many processors to speed a single of obtaining a 10,000-processor supercomputer. For dynamics simulation, have been made and have par- comparison, the largest unclassified supercomputer in tially overcome this divide. A tour-de-force parallel- the world (the SP at NERSC) has 2500 processors, ization of simulation code for supercomputers by Duan and of course this resource must be shared between and Kollman has previously led to the simulation many (hundreds) different research groups. Recently, of 1 ␮s of dynamics for the villin headpiece three- another approach has been developed to bridge this helix bundle,6 demonstrating that parallelization enormous computational gap: worldwide distributed 7 schemes using hundreds of processors can be used to computing. There are hundreds of millions of idle make significant progress at closing this computa- PCs potentially available for use at any given time, tional gap. However, such methods have fundamental the majority of which are vastly underused. These drawbacks: in particular, these methods require com- computers could be used to form the most powerful plex, expensive supercomputers due to the need for supercomputer on the planet by several orders of fast communication between processors. Moreover, magnitude.7 However, to tap into this resource effi- due to the stochastic nature of folding, in order to ciently and productively, we must employ nontradi- study the folding of a 10-␮s folder, one must simulate tional parallelization techniques.8,9 Indeed, we wish to hundreds of microseconds, requiring computing accomplish a seemingly impossible goal: to push the power equal to thousands or tens of thousands of scalability of MD simulations to previously unattain- today’s processors. able levels (i.e., the efficient use of tens of thousands Protein Folding Simulations on the Submillisecond Time Scale 93 of processors) using an extremely heterogeneous net- along the pathway (which have been found in many folding work of processors that are loosely coupled by rela- and unfolding simulations19). Second, these methods re- tively low-tech networking (primarily modems). quire knowledge of the native state as an end goal and in a In this review, we first present the details of our sense apply a field to the trajectories to reach this native method to simulate protein folding using distributed state. Finally, in the end, the heart of the protein folding problem lies in sampling, and even with the great benefits of computing, and then summarize our folding simula- path sampling methodology, a tremendous degree of sam- tion results for several small, fast folding proteins and pling (in this case, in path space) must still be performed. polymers. Specifically, we demonstrate the applica- Thus, the main goal of the method we have developed is bility of our method by simulating the folding of to simulate folding dynamics starting purely from the pro- 10,11 protein helices in atomic detail. Next, as an addi- tein sequence and an atomistic force field, without using any tional quantitative test of our methodology, we exam- knowledge of the native state in the folding simulation. It is ine the folding rate and folding time distribution of a important that our method can successfully tackle the issue nonbiological helix,12 for which results of traditional of lingering in metastable free energy minima. To achieve MD simulations13 and experiments14 are known. We this, we use the following algorithm (“ensemble dynam- finally apply these methods to larger and more com- ics”). Consider running M independent simulations started plex proteins, including a ␤-hairpin15,16 and a three- from a given initial condition (each run starts from the same coordinates, but with different velocities). We next wait for helix bundle.6 We conclude with an assessment of the the first simulation to cross the free energy barrier (see validity of our methods including a quantitative com- Figure 1). Since the average time for the first of M simula- parison of these results with experimental measure- tions to cross a single barrier is M times less than the ments of folding rates and equilibrium constants, and average time for all the simulations (assuming an exponen- a discussion of what we have learned about folding tial distribution of barrier crossing times8,9; see below for mechanisms. details), we can use M processors to effectively achieve an M times speedup of a dynamical simulation, thus avoiding the waiting in free energy minima. In a sense, we distribute the waiting to each processor in parallel, rather than in METHODS series, as in traditional parallel MD. Given
Load more

Recommended publications
  • Simulations of Я-Hairpin Folding Confined to Spherical Pores Using
    Simulations of ␤-hairpin folding confined to spherical pores using distributed computing D. K. Klimov*†, D. Newfield‡, and D. Thirumalai*† *Institute for Physical Science and Technology, University of Maryland, College Park, MD 20742; and ‡Parabon Computation, 3930 Walnut Street, Suite 100, Fairfax, VA 22030-4738 Communicated by George H. Lorimer, University of Maryland, College Park, MD, April 12, 2002 (received for review December 18, 2001) 3 ϱ We report the thermodynamics and kinetics of an off-lattice Go radius of gyration of a chain Rg at D (the size of a chain in ␤ Ӎ ␯ model -hairpin from Ig-binding protein confined to an inert bulk solution) to N according to Rg aN . If the chain is ideal, ␯ ϭ ⌬ ϭ ͞ 2 spherical pore. Confinement enhances the stability of the hairpin then 0.5 and FU RTN(a D) . Because of the reduction due to the decrease in the entropy of the unfolded state. Compared in the translational entropy, confinement also increases the free ⌬ Ͼ ⌬ ͞⌬ ϽϽ with their values in the bulk, the rates of hairpin formation increase energy of the native state, i.e., FN 0. If FN FU 1, then in the spherical pore. Surprisingly, the dependence of the rates on localization of a protein in a confined space stabilizes the native the pore radius, Rs, is nonmonotonic. The rates reach a maximum state compared with the bulk. It also follows that there is a range ͞ b Ӎ b at Rs Rg,N 1.5, where Rg,N is the radius of gyration of the folded of D values over which stability is maximized.
    [Show full text]
  • Structural Mechanisms of Oligomer and Amyloid Fibril Formation by the Prion Protein Cite This: Chem
    ChemComm View Article Online FEATURE ARTICLE View Journal | View Issue Structural mechanisms of oligomer and amyloid fibril formation by the prion protein Cite this: Chem. Commun., 2018, 54,6230 Ishita Sengupta a and Jayant B. Udgaonkar *b Misfolding and aggregation of the prion protein is responsible for multiple neurodegenerative diseases. Works from several laboratories on folding of both the WT and multiple pathogenic mutant variants of the prion protein have identified several structurally dissimilar intermediates, which might be potential precursors to misfolding and aggregation. The misfolded aggregates themselves are morphologically distinct, critically dependent on the solution conditions under which they are prepared, but always b-sheet rich. Despite the lack of an atomic resolution structure of the infectious pathogenic agent in prion diseases, several low resolution models have identified the b-sheet rich core of the aggregates formed in vitro, to lie in the a2–a3 subdomain of the prion protein, albeit with local stabilities that vary Received 17th April 2018, with the type of aggregate. This feature article describes recent advances in the investigation of in vitro Accepted 14th May 2018 prion protein aggregation using multiple spectroscopic probes, with particular focus on (1) identifying DOI: 10.1039/c8cc03053g aggregation-prone conformations of the monomeric protein, (2) conditions which trigger misfolding and oligomerization, (3) the mechanism of misfolding and aggregation, and (4) the structure of the misfolded rsc.li/chemcomm intermediates and final aggregates. 1. Introduction The prion protein can exist in two distinct structural isoforms: a National Centre for Biological Sciences, Tata Institute of Fundamental Research, PrPC and PrPSc.
    [Show full text]
  • Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
    processes Review Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development Outi M. H. Salo-Ahen 1,2,* , Ida Alanko 1,2, Rajendra Bhadane 1,2 , Alexandre M. J. J. Bonvin 3,* , Rodrigo Vargas Honorato 3, Shakhawath Hossain 4 , André H. Juffer 5 , Aleksei Kabedev 4, Maija Lahtela-Kakkonen 6, Anders Støttrup Larsen 7, Eveline Lescrinier 8 , Parthiban Marimuthu 1,2 , Muhammad Usman Mirza 8 , Ghulam Mustafa 9, Ariane Nunes-Alves 10,11,* , Tatu Pantsar 6,12, Atefeh Saadabadi 1,2 , Kalaimathy Singaravelu 13 and Michiel Vanmeert 8 1 Pharmaceutical Sciences Laboratory (Pharmacy), Åbo Akademi University, Tykistökatu 6 A, Biocity, FI-20520 Turku, Finland; ida.alanko@abo.fi (I.A.); rajendra.bhadane@abo.fi (R.B.); parthiban.marimuthu@abo.fi (P.M.); atefeh.saadabadi@abo.fi (A.S.) 2 Structural Bioinformatics Laboratory (Biochemistry), Åbo Akademi University, Tykistökatu 6 A, Biocity, FI-20520 Turku, Finland 3 Faculty of Science-Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands; [email protected] 4 Swedish Drug Delivery Forum (SDDF), Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden; [email protected] (S.H.); [email protected] (A.K.) 5 Biocenter Oulu & Faculty of Biochemistry and Molecular Medicine, University of Oulu, Aapistie 7 A, FI-90014 Oulu, Finland; andre.juffer@oulu.fi 6 School of Pharmacy, University of Eastern Finland, FI-70210 Kuopio, Finland; maija.lahtela-kakkonen@uef.fi (M.L.-K.); tatu.pantsar@uef.fi
    [Show full text]
  • Native-Like Mean Structure in the Unfolded Ensemble of Small Proteins
    B doi:10.1016/S0022-2836(02)00888-4 available online at http://www.idealibrary.com on w J. Mol. Biol. (2002) 323, 153–164 Native-like Mean Structure in the Unfolded Ensemble of Small Proteins Bojan Zagrovic1, Christopher D. Snow1, Siraj Khaliq2 Michael R. Shirts2 and Vijay S. Pande1,2* 1Biophysics Program The nature of the unfolded state plays a great role in our understanding of Stanford University, Stanford proteins. However, accurately studying the unfolded state with computer CA 94305-5080, USA simulation is difficult, due to its complexity and the great deal of sampling required. Using a supercluster of over 10,000 processors we 2Department of Chemistry have performed close to 800 ms of molecular dynamics simulation in Stanford University, Stanford atomistic detail of the folded and unfolded states of three polypeptides CA 94305-5080, USA from a range of structural classes: the all-alpha villin headpiece molecule, the beta hairpin tryptophan zipper, and a designed alpha-beta zinc finger mimic. A comparison between the folded and the unfolded ensembles reveals that, even though virtually none of the individual members of the unfolded ensemble exhibits native-like features, the mean unfolded structure (averaged over the entire unfolded ensemble) has a native-like geometry. This suggests several novel implications for protein folding and structure prediction as well as new interpretations for experiments which find structure in ensemble-averaged measurements. q 2002 Elsevier Science Ltd. All rights reserved Keywords: mean-structure hypothesis; unfolded state of proteins; *Corresponding author distributed computing; conformational averaging Introduction under folding conditions, with some notable exceptions.14 – 16 This is understandable since under Historically, the unfolded state of proteins has such conditions the unfolded state is an unstable, received significantly less attention than the folded fleeting species making any kind of quantitative state.1 The reasons for this are primarily its struc- experimental measurement very difficult.
    [Show full text]
  • Recent Advances in the Structural Biology of the 26S Proteasome
    The International Journal of Biochemistry & Cell Biology 79 (2016) 437–442 Contents lists available at ScienceDirect The International Journal of Biochemistry & Cell Biology jo urnal homepage: www.elsevier.com/locate/biocel Review article Recent advances in the structural biology of the 26S proteasome ∗ Marc Wehmer, Eri Sakata Department of Molecular Structural Biology, Max Planck institute of Biochemistry, 82152, Martinsried, Germany a r t i c l e i n f o a b s t r a c t Article history: There is growing appreciation for the fundamental role of structural dynamics in the function of macro- Received 28 June 2016 molecules. In particular, the 26S proteasome, responsible for selective protein degradation in an ATP Received in revised form 2 August 2016 dependent manner, exhibits dynamic conformational changes that enable substrate processing. Recent Accepted 3 August 2016 cryo-electron microscopy (cryo-EM) work has revealed the conformational dynamics of the 26S protea- Available online 4 August 2016 some and established the function of the different conformational states. Technological advances such as direct electron detectors and image processing algorithms allowed resolving the structure of the pro- Keywords: teasome at atomic resolution. Here we will review those studies and discuss their contribution to our 26S proteasome understanding of proteasome function. Cryoelectron microscopy © 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND Single particle analysis Structural biology license (http://creativecommons.org/licenses/by-nc-nd/4.0/). AAA+ ATPase Contents 1. Introduction . 437 2. Structural dynamics of the 26S proteasome . 438 3. Mechanical insights into the proteasome .
    [Show full text]
  • Topological Distribution of Four-A-Helix Bundles (Folding Motif/Solvent Accessibility/Helix Dipole) SCOTT R
    Proc. NatI. Acad. Sci. USA Vol. 86, pp. 6592-6596, September 1989 Biochemistry Topological distribution of four-a-helix bundles (folding motif/solvent accessibility/helix dipole) SCOTT R. PRESNELL* AND FRED E. COHEN*t Departments of *Pharmaceutical Chemistry and tMedicine, University of California, San Francisco, San Francisco, CA 94143-0446 Communicated by Frederic M. Richards, June 19, 1989 ABSTRACT The four-a-helix bundle, a common struc- suggest a set of bundle structures beyond those initially tural motif in globular proteins, provides an excellent forum for reviewed by Weber and Salemme (8). Further, we will the examination of predictive constraints for protein backbone describe robust topological characterizations and categori- topology. An exhaustive examination of the Brookhaven Crys- zations of the discovered structures. In light of our catego- tallographic Protein Data Bank and other literature sources has rization scheme, the past and current topological constraints lead to the discovery of 20 putative four-a-helix bundles. used for the prediction of protein structures containing four- Application of an analytical method that examines the differ- a-helix bundles are reevaluated. ence between solvent-accessible surface areas in packed and partially unpacked bundles reduced the number of structures to 16. Angular requirements further reduced the list ofbundles METHODS to 13. In 12 of these bundles, all pairs of neighboring helices To locate putative four-a-helix bundles, two independent were oriented in an anti-parallel fashion. This distribution is in observers employed the graphical display program MIDAS accordance with structure types expected if the helix macro (11) to inspect more than 300 globular protein structures from dipole effect makes a substantial contribution to the stability of the Brookhaven Protein Data Bank (12) (November 14, 1988).
    [Show full text]
  • DNA Energy Landscapes Via Calorimetric Detection of Microstate Ensembles of Metastable Macrostates and Triplet Repeat Diseases
    DNA energy landscapes via calorimetric detection of microstate ensembles of metastable macrostates and triplet repeat diseases Jens Vo¨ lkera, Horst H. Klumpb, and Kenneth J. Breslauera,c,1 aDepartment of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Rd, Piscataway, NJ 08854; bDepartment of Molecular and Cell Biology, University of Cape Town, Private Bag, Rondebosch 7800, South Africa; and cCancer Institute of New Jersey, New Brunswick, NJ 08901 Communicated by I. M. Gelfand, Rutgers, The State University of New Jersey, Piscataway, NJ, October 15, 2008 (received for review September 8, 2008) Biopolymers exhibit rough energy landscapes, thereby allowing biological role(s), if any, of kinetically stable (metastable) mi- biological processes to access a broad range of kinetic and ther- crostates that make up the time-averaged, native state ensembles modynamic states. In contrast to proteins, the energy landscapes of macroscopic nucleic acid states remains to be determined. of nucleic acids have been the subject of relatively few experimen- As part of an effort to address this deficiency, we report here tal investigations. In this study, we use calorimetric and spectro- experimental evidence for the presence of discrete microstates scopic observables to detect, resolve, and selectively enrich ener- in metastable triplet repeat bulge looped ⍀-DNAs of potential getically discrete ensembles of microstates within metastable DNA biological significance. The specific triplet repeat bulge looped structures. Our results are consistent with metastable, ‘‘native’’ ⍀-DNA species investigated mimic slipped DNA structures DNA states being composed of an ensemble of discrete and corresponding to intermediates in the processes that lead to kinetically stable microstates of differential stabilities, rather than DNA expansion in triplet repeat diseases (36).
    [Show full text]
  • Density Functional Theory for Protein Transfer Free Energy
    Density Functional Theory for Protein Transfer Free Energy Eric A Mills, and Steven S Plotkin∗ Department of Physics & Astronomy, University of British Columbia, Vancouver, British Columbia V6T1Z4 Canada E-mail: [email protected] Phone: 1 604-822-8813. Fax: 1 604-822-5324 arXiv:1310.1126v1 [q-bio.BM] 3 Oct 2013 ∗To whom correspondence should be addressed 1 Abstract We cast the problem of protein transfer free energy within the formalism of density func- tional theory (DFT), treating the protein as a source of external potential that acts upon the sol- vent. Solvent excluded volume, solvent-accessible surface area, and temperature-dependence of the transfer free energy all emerge naturally within this formalism, and may be compared with simplified “back of the envelope” models, which are also developed here. Depletion contributions to osmolyte induced stability range from 5-10kBT for typical protein lengths. The general DFT transfer theory developed here may be simplified to reproduce a Langmuir isotherm condensation mechanism on the protein surface in the limits of short-ranged inter- actions, and dilute solute. Extending the equation of state to higher solute densities results in non-monotonic behavior of the free energy driving protein or polymer collapse. Effective inter- action potentials between protein backbone or sidechains and TMAO are obtained, assuming a simple backbone/sidechain 2-bead model for the protein with an effective 6-12 potential with the osmolyte. The transfer free energy dg shows significant entropy: d(dg)=dT ≈ 20kB for a 100 residue protein. The application of DFT to effective solvent forces for use in implicit- solvent molecular dynamics is also developed.
    [Show full text]
  • Structural Plasticity of 4-Α-Helical Bundles Exemplified by the Puzzle-Like Molecular Assembly of the Rop Protein
    Structural plasticity of 4-α-helical bundles exemplified by the puzzle-like molecular assembly of the Rop protein Maria Amprazia,b, Dina Kotsifakib, Mary Providakib, Evangelia G. Kapetanioub, Georgios Fellasa, Ioannis Kyriazidisa, Javier Pérezc, and Michael Kokkinidisa,b,1 aDepartment of Biology, University of Crete, GR 71409 Heraklion, Crete, Greece; bInstitute of Molecular Biology and Biotechnology, Foundation of Research and Technology, GR 70013 Heraklion, Crete, Greece; and cSynchrotron SOLEIL, 91192 Gif-sur-Yvette, France Edited by José N. Onuchic, Rice University, Houston, TX, and approved June 20, 2014 (received for review December 12, 2013) The dimeric Repressor of Primer (Rop) protein, a widely used “loopless” mutant, the α-helical hairpin of the monomer is model system for the study of coiled-coil 4-α-helical bundles, is converted into a single helix (15, 16). The complete LLR mol- characterized by a remarkable structural plasticity. Loop region ecule is a tetramer that is completely reorganized relative to the mutations lead to a wide range of topologies, folding states, dimeric wild-type (WT) Rop, thereby becoming a hyper-ther- and altered physicochemical properties. A protein-folding study mostable protein (16). On the other hand, establishment of an of Rop and several loop variants has identified specific residues uninterrupted heptad periodicity through a two-residue insertion and sequences that are linked to the observed structural plasticity. in the loop produces minimal changes relative to WT in terms of Apart from the native state, native-like and molten-globule states structure and properties (12). Thus, these two mutants with have been identified; these states are sensitive to reducing agents uninterrupted patterns of heptads reveal that there is a consid- due to the formation of nonnative disulfide bridges.
    [Show full text]
  • Computational Redox Potential Predictions: Applications to Inorganic and Organic Aqueous Complexes, and Complexes Adsorbed to Mineral Surfaces
    Minerals 2014, 4, 345-387; doi:10.3390/min4020345 OPEN ACCESS minerals ISSN 2075-163X www.mdpi.com/journal/minerals Review Computational Redox Potential Predictions: Applications to Inorganic and Organic Aqueous Complexes, and Complexes Adsorbed to Mineral Surfaces Krishnamoorthy Arumugam and Udo Becker * Department of Earth and Environmental Sciences, University of Michigan, 1100 North University Avenue, 2534 C.C. Little, Ann Arbor, MI 48109-1005, USA; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-734-615-6894; Fax: +1-734-763-4690. Received: 11 February 2014; in revised form: 3 April 2014 / Accepted: 13 April 2014 / Published: 24 April 2014 Abstract: Applications of redox processes range over a number of scientific fields. This review article summarizes the theory behind the calculation of redox potentials in solution for species such as organic compounds, inorganic complexes, actinides, battery materials, and mineral surface-bound-species. Different computational approaches to predict and determine redox potentials of electron transitions are discussed along with their respective pros and cons for the prediction of redox potentials. Subsequently, recommendations are made for certain necessary computational settings required for accurate calculation of redox potentials. This article reviews the importance of computational parameters, such as basis sets, density functional theory (DFT) functionals, and relativistic approaches and the role that physicochemical processes play on the shift of redox potentials, such as hydration or spin orbit coupling, and will aid in finding suitable combinations of approaches for different chemical and geochemical applications. Identifying cost-effective and credible computational approaches is essential to benchmark redox potential calculations against experiments.
    [Show full text]
  • Conformational Search for the Protein Native State
    CHAPTER 19 CONFORMATIONAL SEARCH FOR THE PROTEIN NATIVE STATE Amarda Shehu Assistant Professor Dept. of Comp. Sci. Al. Appnt. Dept. of Comp. Biol. and Bioinf. George Mason University 4400 University Blvd. MSN 4A5 Fairfax, Virginia, 22030, USA Abstract This chapter presents a survey of computational methods that obtain a struc- tural description of the protein native state. This description is important to understand a protein's biological function. The chapter presents the problem of characterizing the native state in conformational detail in terms of the chal- lenges that it raises in computation. Computing the conformations populated by a protein under native conditions is cast as a search problem. Methods such as Molecular Dynamics and Monte Carlo are treated rst. Multiscaling, the combination of reduced and high complexity models of conformations, is briey summarized as a powerful strategy to rapidly extract important fea- tures of the energy surface associated with the protein conformational space. Other strategies that narrow the search space through information obtained in the wet lab are also presented. The chapter then focuses on enhanced sam- Protein Structure Prediction:Method and Algorithms. By H. Rangwala & G. Karypis 1 Copyright c 2013 John Wiley & Sons, Inc. 2 CONFORMATIONAL SEARCH FOR THE PROTEIN NATIVE STATE pling strategies employed to compute native-like conformations when given only amino-acid sequence. Fragment-based assembly methods are analyzed for their success and what they are revealing about the physical process of folding. The chapter concludes with a discussion of future research directions in the computational quest for the protein native state. 19.1 THE QUEST FOR THE PROTEIN NATIVE STATE From the rst formulation of the protein folding problem by Wu in 1931 to the experiments of Mirsky and Pauling in 1936, chemical and physical properties of protein molecules were attributed to the amino-acid composition and structural arrangement of the protein chain [86, 56].
    [Show full text]
  • Principles of Helix-Helix Packing in Proteins: the Helical Lattice Superposition Model Dirk Walther1*, Frank Eisenhaber1,2 and Patrick Argos1
    J. Mol. Biol. (1996) 255, 536–553 Principles of Helix-Helix Packing in Proteins: The Helical Lattice Superposition Model Dirk Walther1*, Frank Eisenhaber1,2 and Patrick Argos1 1European Molecular Biology The geometry of helix-helix packing in globular proteins is comprehen- Laboratory, Meyerhofstraße 1 sively analysed within the model of the superposition of two helix lattices Postfach 10.2209, 69012 which result from unrolling the helix cylinders onto a plane containing Heidelberg, Germany points representing each residue. The requirements for the helix geometry (the radius R, the twist angle v and the rise per residue D) under perfect 2Biochemisches Institut der match of the lattices are studied through a consistent mathematical model Charite´, der Humboldt- that allows consideration of all possible associations of all helix types (a-, Universita¨t zu Berlin, p- and 310). The corresponding equations have three well-separated Hessische Straße 3–4 10115 solutions for the interhelical packing angle, V, as a function of the helix Berlin, Germany geometric parameters allowing optimal packing. The resulting functional relations also show unexpected behaviour. For a typically observed a-helix ° − ° (v = 99.1 , D = 1.45 Å), the three optimal packing angles are Va,b,c = 37.1 , −97.4° and +22.0° with a periodicity of 180° and respective helix radii Ra,b,c = 3.0 Å, 3.5 Å and 4.3 Å. However, the resulting radii are very sensitive ° to variations in the twist angle v. At vtriple = 96.9 , all three solutions yield identical radii at D = 1.45 Å where Rtriple = 3.46 Å. This radius is close to that of a poly(Ala) helix, indicating a great packing flexibility when alanine is involved in the packing core, and vtriple is close to the mean observed twist angle.
    [Show full text]