UNIVERSITAT POLITÈCNICA DE CATALUNYA DEPARTAMENT D’ENGINYERIA QUÍMICA APPLICATION OF MOLECULAR SIMULATION TECHNIQUES TO THE DESIGN OF NANOSYSTEMS Francisco Rodríguez Ropero Advisors: Dr.Carlos Alemán Llansó y Dr. David Zanuy Gómara Barcelona, September 2009 i OBJECTIVES (1) Improve the stability of tubular nanodevices based on highly regular β-helical motifs excised from naturally occurring proteins by replacing targeted natural residues by conformationally constrained synthetic amino acids. (2) Model and characterize a dendronized polymethacrylate carrying second generation chiral 4-aminoproline-based dendrons and a thiophene based dendronized polymer in order to explain, in basis of their structure, the extraordinary stiffness of the first and the great conductivity exhibited by the latter in previous experimental studies. (3) Study of the interactions of thiophene based conducting polymers. The interaction of these polymers with the solvent medium as well as their intermolecular interactions such as π-stacking interactions play a key role when designing new devices based on conducting polymers. (4) Exploit the intrinsic tubular geometry of natural motifs extracted from certain proteins together with the ability of π-conjugated systems to promote charge transfer to model a tubular electronic conductor based on natural peptide sequences by replacing natural amino acids by synthetic amino acids owning an aromatic side chain. (5) Study of the role played by the solvent molecules in the actuation mechanism in the molecular actuator poly(calix[4]arene bis-bithiophene) by the examination of the structure and dynamics of the dichloromethane solvent around the calix[4]arene units. (6) Investigation of the selectivity of a polythiophene functionalized with calix[4]arene nanosensor at the microscopic level which experimentally presents a great selectivity towards Na+ with respect to K+ and Li+ alkaline cations. iii ABBREVIATIONS 1hv9 residues 296-329 of N-acetylglucosamine 1-phosphate uridyltransferase GlmU, C-terminal domain from Eschericia coli 1krr Residues 131-165 of the chain A from the Escherichia coli galactoside acetyltransferase Ac3c 1-aminocyclopropane-1-carboxylic acid Ac4c 1-aminocyclobutane-1-carboxylic acid Ac5c 1-aminocyclopentane-1-carboxylic acid Ac6c 1-aminocyclohexane-1-carboxylic acid Acnc 1-aminocycloalkane-1-carboxylic acids Aib -aminoisobutyric acid AIBN 2,2’-azobisisobutyronitrile AIMI Aromatic Intermolecular Interaction Model AM1 Austin Model number 1 B3LYP Becke’s three parameter hybrid functional with the Lee, Yang and Parr expression. Boc tert-butoxycarbonyl BSSE Basis Set Superposition Error c3Dip 1-amino-2,2-diphenyl-cyclopropanecarboxylic acid CC Coupled Cluster CCSD(T) Coupled cluster singles, doubles and triples method being the contribution of triple excitations represented in an approximate way CD Circular Dichroism CP Counterpoise DFT Density Functional Theory DSC Differential Scanning Calorimetry Dg Diphenylglycine ESP Electrostatic potential FF Force Field GGA Generalised Gradient Approximation Ĥ Hamiltonian operator HF Hartree Fock HOMO Highest Occupied Molecular Orbital IP Ionization Potential iv KT Koopman’s Theorem LCAO Linear Combination of Atomic Orbitals LDA Local Density Approximation LSCF Local Self-Consistent Field LSDA Local Spin Density Approximation LUMO Lowest Unoccupied Molecular Orbital MD Molecular Dynamics MEP Molecular Electrostatic Potential MGn nth Generation monomer (dendron) MM Molecular Mechanics MP Møller Plesset NA9PH 9-(2,3-dihydro-2-phenyl-1H-benz[e]inden-1-ylidene)-9H-fluorene NA9PH(S) NA9PH Singlet state NA9PH(T) NA9PH Triplet state NPT Isobaric-isothermal ensemble NVT Canonical ensemble OR Optical Rotation PCM Polarizable Continuum Model PDB Protein Data Bank th PGn nGeneration polymer (dendronized polymer) PM3 Parameterized Model number 3 PME Particle Mesh Ewald PMF Potential Mean Force PMMA Poly(methyl methacrylate) QM Quantum Mechanics QM/MM Quantum mechanics/Molecular mechanics RESP Restrained Electrostatic Potential RMSD Root Mean Square Deviation RMSF Root Mean Square Fluctuation r.u. Repeat Unit SCF Self Consistent Field SCRF Self Consistent Reaction Field SDTQ Single, Double, Triple and Quadruple Excitations v SE Semiempirical SLBO Strictly Localized Bond Orbitals STO Slater Type Orbital TD Time-dependent Tie β-3-thienylalanine UB3LYP Unrestricted B3LYP UHF Unrestricted Hartree Fock UMP2 Unrestricted MP2 UPM3 Unrestricted PM3 wt Wild type ZPVE Zero-Point Vibrational Energies Ala-Alanine Ala Dehydroalanine vii TABLE OF CONTENTS 1. Introduction ..........................................................................................1 1.1. A brief description of nanotechnology: history and current state ........................ 3 1.2. Presence of nanotechnology: applications............................................................ 5 1.3. Role of Computational Chemistry in the development of nanodevices ............... 7 1.4. References .......................................................................................................... 10 2. Methodology........................................................................................15 2.1. Computational chemistry.................................................................................... 17 2.2. Quantum Mechanical Methods........................................................................... 18 2.2.1. Hamiltonian operator.................................................................................. 18 2.2.2. Basis sets.................................................................................................... 19 2.2.3. Closed-shell and open-shell systems .......................................................... 21 2.2.4. Ab initio calculations.................................................................................. 21 2.2.5. Semiempirical calculations......................................................................... 23 2.2.6. Density Functional Theory calculations..................................................... 24 2.2.7. Solvent effects............................................................................................ 25 2.3. Molecular dynamics simulations........................................................................ 27 2.3.1. Force-Field ................................................................................................. 27 2.3.2. Mathematical model of molecular dynamics.............................................. 28 2.3.3. Thermodynamic ensembles ........................................................................ 29 2.3.4. Periodic boundary conditions and Particle Mesh-Ewald Summation ........ 30 2.4. QM/MM calculations......................................................................................... 31 2.5. References .......................................................................................................... 33 3. Nanotubes based on natural peptide sequences ..............................37 3.1. Testing β–helix terminal coils stability by targeted substitutions with non- proteogenic amino acids: A Molecular Dynamics study............................................ 39 3.1.1. Introduction ................................................................................................ 39 3.1.2. Survey of Synthetic Amino Acids.............................................................. 43 3.1.3. Methods ...................................................................................................... 44 3.1.4. Results and discussion................................................................................ 47 3.1.5. Conclusions ................................................................................................ 55 viii 3.1.6. References .................................................................................................. 57 3.2. Stability of tubular structures based on β-helical proteins: self-assembled versus polymerized nanoconstructs and wild-type versus mutated sequences...................... 60 3.2.1. Introduction ................................................................................................ 60 3.2.2. Description of the β-helical building blocks and the Ac5c synthetic residue……………………………………………………………………………. 62 3.2.3. Methods ...................................................................................................... 63 3.2.4. Results and discussion................................................................................ 66 3.2.5. Conclusions ................................................................................................ 79 3.2.6. References .................................................................................................. 80 3.3. Application of 1-aminocyclohexane carboxylic acid to protein nanostructure computer design.......................................................................................................... 83 3.3.1. Introduction ................................................................................................ 83 3.3.2. Methods ...................................................................................................... 85 3.3.3. Results and discussion................................................................................ 88 3.3.4. Conclusions .............................................................................................. 104 3.3.5. References ...............................................................................................