Improved treatment of cyclic β‐amino acids and successful prediction of β‐peptide secondary structure using a modified force field: AMBER*C

We added parameters to the AMBER* force field to model cyclic β‐amino acid derivatives more accurately within the commonly used MacroModel program. In an effort to generate an improved treatment of cyclohexane and cyclopentane conformational preferences, carbon–carbon torsional parameters were modified and incorporated into a force field we call AMBER*C. Simulation of trans‐2‐aminocyclohexanecarboxylic acid (trans‐ACHC) and trans‐2‐aminocyclopentanecarboxylic acid (trans‐ACPC) derivatives using AMBER*C produces more realistic energy differences between (pseudo)diaxial and (pseudo)diequatorial conformations than does simulation using AMBER*. AMBER*C molecular dynamics simulations more accurately reproduce the experimental hydrogen‐bonding tendencies of simple diamide derivatives of trans‐ACHC and trans‐ACPC than do simulations using the AMBER* force field. More importantly, this modified force field allows accurate qualitative prediction of the helical secondary structures adopted by β‐amino acid homo‐oligomers. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 763–773, 2000     

Reversible peptide folding: Dependence on molecular force field used

Temperature‐dependent nuclear magnetic resonance (NMR) and CD spectra of methanol solutions of a β‐heptapeptide have been interpreted in such a way that the secondary structure, a 3₁₄‐helix, is assumed to be stable in a temperature range of between 298 and 393 K. This is in contrast to the results of a 50‐ns molecular dynamics simulation using the GROMOS 96 force field, which found a melting temperature of about 340 K. This discrepancy is addressed by further computational studies using the OPLS‐AA force field. The conformational energetics of N‐formyl‐3‐aminobutanamide in vacuo are obtained using ab initio and density functional quantum‐mechanical calculations at the HF/6‐31G*, B3LYP/6‐31G*, and B3LYP/6‐311+G* levels of theory. The results permit development of torsional parameters for the OPLS‐AA force field that reproduce the conformational energetics of the monomer. By varying the development procedure, three parameter sets are obtained that focus on reproducing either low‐energy or high‐energy conformations. These parameter sets are tested by simulating the reversible folding of the β‐heptapeptide in methanol. The melting temperature of the helix formed (>360 K) is found to be higher than the one obtained from simulations using the GROMOS 96 force field (∼340 K). Differences in the potential energy functions of the latter two force fields are evaluated and point to the origins of the difference in stability. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 774–787, 2000     

Bis(dichlorosilyl)methylamine – Synthesis,Crystal Structure,and Conformational Analysis in the Gas Phase

A straightforward preparation has been found for bis(dichlorosilyl)methylamine, (SiHCl₂)₂NMe ( 1 ), involving reaction between H₂NMe and an excess of SiHCl₃, dissolved either in pentane or THF at 253 K. 1 and a side‐product, 1,3,5‐trichloro‐2,4,6‐trimethylcyclotrisilazane, (–SiHCl–NMe–)₃ ( 2 ), were identified by elemental analysis, mass spectrometry and ¹H‐NMR‐spectroscopy. Some physical, NMR‐ and IR spectroscopical properties of 1 were determined. The molecular and crystal structure of 1 was investigated by single crystal X‐ray diffraction. Selected structural parameters: r(Si–N) 169.7(5), r(Si–Cl) 203.1(2)–204.4(2), r(C–N) 150.0(8) pm; a(SiNSi) 123.6(3), a(SiNC) 118.3(4)/118.0(4)°. Ab initio force field data and infrared intensities were calculated for four conformers of 1 . Comparison of the observed and calculated IR spectra favours the two structures found ab initio provided that their actual abundancies are different from those calculated.     

An improved GROMOS96 force field for aliphatic hydrocarbons in the condensed phase

Over the past 4 years the GROMOS96 force field has been successfully used in biomolecular simulations, for example in peptide folding studies and detailed protein investigations, but no applications to lipid systems have been published yet. Here we provide a detailed investigation of aliphatic liquid systems. For liquids of larger aliphatic chains, n‐heptane and longer, the standard GROMOS96 parameter sets 43A1 and 43A2 yield a too low pressure at the experimental density. Therefore, a reparametrization of the GROMOS96 force field regarding aliphatic carbons was initiated. The new force field parameter set 45A3 shows considerable improvements for n‐alkanes, cyclo‐, iso‐, and neoalkanes and other branched aliphatics. Liquid densities and heat of vaporization are reproduced for almost all of these molecules. Excellent agreement is found with experiment for the free energy of hydration for alkanes. The GROMOS96 45A3 parameter set should, therefore, be suitable for application to lipid aggregates such as membranes and micelles, for mixed systems of aliphatics with or without water, for polymers, and other apolar systems that may interact with different biomolecules. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1205–1218, 2001     

Cracking of n‐octadecane: A molecular dynamics simulation

Despite the extensive research studies, the understanding of the fundamental mechanisms of chemical transformations at the cracking of hydrocarbons remains unexplored. In the present study, the initial stages of both thermal and catalytic cracking of n‐octadecane C₁₈H₃₈ (with a nickel Ni₄₉ particle as a catalyst) were investigated using the ReaxFF force field (the ReaxFF software package). The initial cracking mechanism of n‐octadecane was simulated at four different temperatures 1,800, 1,900, 2,000, and 2,200 K on a large interface system (2,849 atoms) consisting of 49 nickel atoms surrounded by 50 hydrocarbon molecules. Analysis of trajectories, according to the simulations, reveals a complex mechanism for initiating thermal and catalytic cracking of C₁₈H₃₈. Thermal cracking of C₁₈H₃₈ is initiated by breaking the C–C bond and proceeds via a free‐radical mechanism, whereas catalytic cracking is preferentially activated by deprotonation and protonation of the C–C bond. This work demonstrates that the ReaxFF force field can be actively used in the study of complex chemical transformations that occur at the cracking of hydrocarbons.     

Assessment of biomolecular force fields for molecular dynamics simulations in a protein crystal

Different biomolecular force fields (OPLS‐AA, AMBER03, and GROMOS96) in conjunction with SPC, SPC/E and TIP3P water models are assessed for molecular dynamics simulations in a tetragonal lysozyme crystal. The root mean square deviations for the C_a atoms of lysozymes are about 0.1 to 0.2 nm from OPLS‐AA and AMBER03, smaller than 0.4 nm from GROMOS96. All force fields exhibit similar pattern in B‐factors, whereas OPLS‐AA and AMBER03 accurately reproduce experimental measurements. Despite slight variations, the primary secondary structures are well conserved using different force fields. Water diffusion in the crystal is approximately ten‐fold slower than in bulk phase. The directional and average water diffusivities from OPLS‐AA and AMBER03 along with SPC/E model match fairly well with experimental data. Compared to GROMOS96, OPLS‐AA and AMBER03 predict larger hydrophilic solvent‐accessible surface area of lysozyme, more hydrogen bonds between lysozyme and water, and higher percentage of water in hydration shell. SPC, SPC/E and TIP3P water models have similar performance in most energetic and structural properties, but SPC/E outperforms in water diffusion. While all force fields overestimate the mobility and electrical conductivity of NaCl, a combination of OPLS‐AA for lysozyme and the Kirkwood‐Buff model for ions is superior to others. As attributed to the steric restraints and surface interactions, the mobility and conductivity in the crystal are reduced by one to two orders of magnitude from aqueous solution. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

On the Reliability of the AMBER Force Field and its Empirical Dispersion Contribution for the Description of Noncovalent Complexes

The reliability of the AMBER force field is tested by comparing the total interaction energy and dispersion energy with the reference data obtained at the density functional theory–symmetry‐adapted perturbation treatment (DFT–SAPT)/aug‐cc‐pVDZ level. The comparison is made for 194 different geometries of noncovalent complexes (H‐bonded, stacked, mixed, and dispersion‐bound), at the equilibrium distances as well as at longer distances (up to a relative distance of two). The total interaction energies agree very well with the reference data and only the strength of H‐bonded complexes is slightly underestimated. In the case of dispersion energy, the overall agreement is even better, with the exception of the stacked aromatic systems, where the empirical dispersion energy is overestimated. The use of AMBER interaction energy and AMBER dispersion energy for different types of noncovalent complexes at equilibrium as well as at longer distances is thus justified, except for a few cases, such as the water molecule, where the dispersion energy is highly inaccurate.     

Theoretical study of disubstituted pyrrolopyrimidines as focal adhesion kinase inhibitors

An in silico molecular modeling study of selected 7H‐pyrrolo[2,3‐d]pyrimidines with FAK inhibitory activities was performed. Rigid docking of each inhibitor at the FAK catalytic site was employed to obtain the most appropriate starting structures, followed by molecular mechanics‐based energy minimizations associated with molecular dynamics at the FAK binding site using the AMBER force field. Theoretical values of interaction energies obtained from the geometry optimization calculations for the protein‐inhibitor complexes were compared with published IC₅₀ values for FAK and showed a reasonable correlation. Based on these results and in view of the geometry of the most potent inhibitors, two new molecular structures were designed as possible FAK inhibitors and submitted to the same theoretical procedures. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Calibration of force-field dependency in free energy landscapes of peptide conformations by quantum chemical calculations

The free energy landscapes of peptide conformations were calibrated by ab initio quantum chemical calculations, after the enhanced conformational diversity search using the multicanonical molecular dynamics simulations. Three different potentials of mean force for an isolated dipeptide were individually obtained by the multicanonical molecular dynamics simulations using the conventional force fields, AMBER parm94, AMBER parm96, and CHARMm22. Each potential of mean force was then calibrated based upon the umbrella sampling algorithm from the adiabatic energy map that was calculated separately by the ab initio molecular orbital method, and all of the calibrated potentials of mean force coincided well. The calibration method was also applied to the simulations of a peptide dimer in explicit water models, and it was shown that the calibrated free energy landscapes did not depend on the force field used in the classical simulations, as far as the conformational space was sampled well. The current calibration method fuses the classical free energy calculation with the quantum chemical calculation, and it should generally make simulations for biomolecular systems much more reliable when combining with enhanced conformational sampling.     

Electrostatic component of binding energy: Interpreting predictions from poisson–boltzmann equation and modeling protocols

Macromolecular interactions are essential for understanding numerous biological processes and are typically characterized by the binding free energy. Important component of the binding free energy is the electrostatics, which is frequently modeled via the solutions of the Poisson–Boltzmann Equations (PBE). However, numerous works have shown that the electrostatic component (ΔΔG_elec) of binding free energy is very sensitive to the parameters used and modeling protocol. This prompted some researchers to question the robustness of PBE in predicting ΔΔG_elec. We argue that the sensitivity of the absolute ΔΔG_elec calculated with PBE using different input parameters and definitions does not indicate PBE deficiency, rather this is what should be expected. We show how the apparent sensitivity should be interpreted in terms of the underlying changes in several numerous and physical parameters. We demonstrate that PBE approach is robust within each considered force field (CHARMM‐27, AMBER‐94, and OPLS‐AA) once the corresponding structures are energy minimized. This observation holds despite of using two different molecular surface definitions, pointing again that PBE delivers consistent results within particular force field. The fact that PBE delivered ΔΔG_elec values may differ if calculated with different modeling protocols is not a deficiency of PBE, but natural results of the differences of the force field parameters and potential functions for energy minimization. In addition, while the absolute ΔΔG_elec values calculated with different force field differ, their ordering remains practically the same allowing for consistent ranking despite of the force field used. © 2016 Wiley Periodicals, Inc.     

Molecular mechanics (MM3) parameterization for oxocarbenium ions

The physical properties of a diverse group of 12 oxocarbenium ions have been studied with ab initio calculations at the MP2/6‐31+G* level of theory. Based on theoretically derived properties such as molecular equilibrium geometry, dipole moment, and vibrational frequencies, a molecular mechanics (MM3) force field has been developed with the assistance of the programs TORSMART and MPMSR, components of our artificial parameter development and refinement method. The MM3 force field is now able to reproduce bond lengths, bond angles, moments of inertia, dipole moments, torsional energy profiles, and vibrational frequencies of oxocarbenium ions, which will allow further studies of glycoside hydrolysis and their rates of reaction. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 329–339, 2000     

Reparameterizations of the χ Torsion and Lennard‐Jones σ Parameters Improve the Conformational Characteristics of Modified Uridines

The currently available force field parameters for modified RNA residues in AMBER show significant deviations in conformational properties from experimental observations. The examination of the transferability of the recently revised torsion parameters revealed that there was an overall improvement in the conformational properties for some of the modifications but the improvements were still insufficient in describing the sugar pucker preferences (J. Chem. Inf. Model. 2014, 54, 1129–1142). Here, we report an approach for the development and fine tuning of the AMBER force field parameters for 2‐thiouridine, 4‐thiouridine, and pseudouridine with diverse conformational preferences. The χ torsion parameters were reparameterized at the individual nucleoside level. The effect of combining the revised γ torsion parameter and modifying the Lennard‐Jones σ parameters were also tested by directly comparing the conformational preferences obtained from our extensive molecular dynamics simulations with those from experimental observations. © 2016 Wiley Periodicals, Inc.     

Computer simulations of ligand–protein binding with ensembles of protein conformations: A Monte Carlo study of HIV‐1 protease binding energy landscapes

We present the results of molecular docking simulations with HIV‐1 protease for the sb203386 and skf107457 inhibitors by Monte Carlo simulated annealing. A simplified piecewise linear energy function, the standard AMBER force field, and the AMBER force field with solvation and a soft‐core smoothing component are employed in simulations with a single‐protein conformation to determine the relationship between docking simulations with a simple energy function and more realistic force fields. The temperature‐dependent binding free energy profiles of the inhibitors interacting with a single protein conformation provide a detailed picture of relative thermodynamic stability and a distribution of ligand binding modes in agreement with experimental crystallographic data. Using the simplified piecewise linear energy function, we also performed Monte Carlo docking simulations with an ensemble of protein conformations employing preferential biased sampling of low‐energy protein conformations, and the results are analyzed in connection with the free energy profiles. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 72: 73–84, 1999     

Quantum mechanical studies on model α‐pleated sheets

Pauling and Corey proposed a pleated‐sheet configuration, now called α‐sheet, as one of the protein secondary structures in addition to α‐helix and β‐sheet. Recently, it has been suggested that α‐sheet is a common feature of amyloidogenic intermediates. We have investigated the stability of antiparallel β‐sheet and two conformations of α‐sheet in solution phase using the density functional theoretical method. The peptides are modeled as two‐strand acetyl‐(Ala)₂‐N‐methylamine. Using stages of geometry optimization and single point energy calculation at B3LYP/cc‐pVTZ//B3LYP/6‐31G* level and including zero‐point energies, thermal, and entropic contribution, we have found that β‐sheet is the most stable conformation, while the α‐sheet proposed by Pauling and Corey has 13.6 kcal/mol higher free energy than the β‐sheet. The α‐sheet that resembles the structure observed in molecular dynamics simulations of amyloidogenic proteins at low pH becomes distorted after stages of geometry optimization in solution. Whether the α‐sheets with longer chains would be increasingly favorable in water relative to the increase in internal energy of the chain needs further investigation. Different from the quantum mechanics results, AMBER parm94 force field gives small difference in solution phase energy between α‐sheet and β‐sheet. The predicted amide I IR spectra of α‐sheet shows the main band at higher frequency than β‐sheet. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Harmonic force field for glycine oligopeptides

The need for much more useful molecular dynamics simulations of nanosized system requires precise and unambiguous methods to determine force field parameters avoiding fitting procedures in favor of first principles ones. We use a procedure FUERZA to calculate force constant parameters for glycine oligopeptides using as an input the Hessian tensor from an ab initio calculation. For a molecular system having n atoms, The FUERZA procedure reduces the 3n × 3n problem to 3n 3 × 3 matrices representing atom‐atom interactions. The procedure reproduces quite well most of the frequencies and as expected, it overestimates somehow stretching frequencies of bonds with terminal atoms such as hydrogens but it yields precise results for all other frequencies. A harmonic force field is reported for glycine oligopeptides. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

An interaction potential to study the thermal structure evolution of a thermoelectric material: β‐Cu2Se

An interaction potential model has been developed, for the first time, for β‐Cu₂Se using the ab initio derived data. The structure and elastic constants of β‐Cu₂Se using the derived force‐field are within a few percent of DFT derived structure and elastic constants and reported experimental structure. The derived force‐field also shows remarkable ability to reproduce temperature dependent behavior of the specific heat and thermal expansion coefficient. The thermal structure evolution of the β‐Cu₂Se is studied by performing the molecular dynamic simulations using the derived force‐field. The simulation results demonstrate that the Cu ions moves around the equilibrium lattice position within the temperature range of 500–800 K. However, at a temperature > 800 K, the Cu ions starts diffusing within the material, while the Se ions remains in their lattice position. The evaluated thermodynamic properties such as free energy and excess entropy, show that the increased Cu–Se interaction with the temperature makes the system more thermodynamically stable. © 2017 Wiley Periodicals, Inc.     

Structure and Thermodynamics of Mg:Phosphate Interactions in Water: A Simulation Study

The association of Mg²⁺ and H₂PO₄^? in water can give insights into Mg:phosphate interactions in general, which are very widespread, but for which experimental data is surprisingly sparse. It is studied through molecular dynamics simulations (>100 ns) by using the polarizable AMOEBA force field, and the association free energy is computed for the first time. Explicit consideration of outer‐sphere and two types of inner‐sphere association provides considerable insight into the dynamics and thermodynamics of ion pairing. After careful assessment of the computational approximations, the agreement with experimental values indicates that the methodology can be extended to other inorganic and biological Mg:phosphate interactions in solution.     

Definitive heat of formation of methylenimine,CH2NH,and of methylenimmonium ion,CH2NH2+, by means of W2 theory

A long‐standing controversy concerning the heat of formation of methylenimine has been addressed by means of the W2 (Weizmann‐2) thermochemical approach. Our best calculated values, ΔH°_f,298(CH₂NH) = 21.1±0.5 kcal/mol and ΔH°_f,298(CH₂NH₂⁺) = 179.4±0.5 kcal/mol, are in good agreement with the most recent measurements but carry a much smaller uncertainty. As a byproduct, we obtain the first‐ever accurate anharmonic force field for methylenimine: upon consideration of the appropriate resonances, the experimental gas‐phase band origins are all reproduced to better than 10 cm^?1. Consideration of the difference between a fully anharmonic zero‐point vibrational energy and B3LYP/cc‐pVTZ harmonic frequencies scaled by 0.985 suggests that the calculation of anharmonic zero‐point vibrational energies can generally be dispensed with, even in benchmark work, for rigid molecules. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1297–1305, 2001     

Interaction potential models for bulk Zns,Zns nanoparticle,and Zns nanoparticle‐PMMA from first‐principles

An ab initio derived transferable polarizable force‐field has been developed for Zinc sulphide (ZnS) nanoparticle (NP) and ZnS NP‐PMMA nanocomposite. The structure and elastic constants of bulk ZnS using the new force‐field are within a few percent of experimental observables. The new force‐field show remarkable ability to reproduce structures and nucleation energies of nanoclusters (Zn₁S₁‐Zn₁₂S₁₂) as validated with that of the density functional theory calculations. A qualitative agreement of the radial distribution functions of Zn? O, in a ZnS nanocluster‐PMMA system, obtained using molecular mechanics molecular dynamics (MD) and ab initio MD (AIMD) simulations indicates that the ZnS–PMMA interaction through Zn? O bonding is explained satisfactorily by our force‐field. © 2015 Wiley Periodicals, Inc.