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Abstract: Recently, stereoinversions and isomerizations of amino acid residues in the proteins of living beings have been observed. Because isomerized amino acids cause structural changes and denaturation of proteins, isomerizations of amino acid residues are suspected to cause age‐related diseases. In this study, AMBER molecular force field parameters were tested by using computationally generated nonapeptides and tripeptides including stereoinverted and/or isomerized amino acid residues. Energy calculations by using density functional theory were also performed for comparison. Although the force field parameters were developed by parameter fitting for l‐α‐amino acids, the accuracy of the computational results for d‐amino acids and β‐amino acids was comparable to those for l‐α‐amino acids. The conformational energies for tripeptides calculated by using density functional theory were reproduced more accurately than those for nonapeptides calculated by using the molecular mechanical force field. The evaluations were performed for the ff99SB, ff03, ff12SB, and the latest ff14SB force field parameters. [ABSTRACT FROM AUTHOR]

The fully polarizable, multipolar, and atomistic force field protein FFLUX is being built from machine learning (i.e., kriging) models, each of which predicts an atomic property. Each atom of a given protein geometry needs to be assigned such a kriging model. Such a knowledgeable atom needs to be informed about a sufficiently large environment around it. The resulting complexity can be tackled by collecting the 20 natural amino acids into a few groups. Using substituted deca-alanines, we present the proof-of-concept that a given atom's charge can be modeled by a few kriging models only. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Molecular dynamics (MD) simulation can give a detailed picture of conformational equilibria of biomolecules, but it is only reliable if the force field used in the simulation is accurate, and the sampling of the conformational space accessible to the biomolecule shows many (un)folding transitions to allow for precise averages of observable quantities. Here, the use of coarse-grained (CG) solvent MeOH and H2O models to speed up the sampling of the conformational equilibria of an octa- β-peptide is investigated. This peptide is thought to predominantly adopt a 314-helical fold when solvated in MeOH, and a hairpin fold when solvated in H2O on the basis of the NMR data. Various factors such as the chirality of a residue, a force-field modification for the solute, coarse-graining of the solvent model, and an extension of the nonbonded interaction cut-off radius are shown to influence the simulated conformational equilibria and the agreement with the experimental NMR data for the octa- β-peptide. [ABSTRACT FROM AUTHOR]

We benchmark the performance of various computational approaches, ranging from the classical nonpolarizable force fields AMBER FF96 and FF99SB, the polarizable force fields AMBER FF02polEP and AMOEBAbio09 to the semiempirical DFT method SCC-DFTB. The test set consists of nine conformations of gas-phase protonated gramicidin S, a cyclic decapeptide. We discuss their structural features in relation to the intrinsic lowest energy structure, which has been solved recently by a combination of cold ion spectroscopy and high level theoretical methods (Nagornova et al., Angew Chem Int Ed 2011, 50, 5383). As a reference, we use the energetics at the M05-2X level of theory. The latter has been validated as a suitable reference method in predicting the correct ground state structure of gas-phase protonated bare and microsolvated tryptophan as well as gas-phase protonated gramicidin S by comparison to experiment. We discuss the performance of the different more approximate methods in relation to their potential use as efficient and reliable tools to explore conformational space for the generation of candidate structures before refinement at the DFT level. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Considering N-methylacetamide (NMA) as a model compound, new interaction parameters are developed for the amide function in the GROMOS force field that are compatible with the recently derived 53A6OXY parameter set for oxygen-containing chemical functions. The resulting set, referred to as 53A6OXY+A, represents an improvement over earlier GROMOS force-field versions in the context of the pure-liquid properties of NMA, including the density, heat of vaporization, dielectric permittivity, self-diffusion constant and viscosity, as well as in terms of the Gibbs hydration free energy of this molecule. Assuming that NMA represents an adequate model compound for the backbone of peptides, 53A6OXY+A may be expected to also provide an improved description of polypeptide chains. As an initial test, simulations are reported for two β-peptides characterized by very different folding properties in methanol. For these systems, earlier force-field versions provided good agreement with experimental NMR data, and the test shows that the improved description achieved in the context of NMA is not accompanied by any deterioration in the representation of the conformational properties of these peptides. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Peptoids are originally defined as N-substituted oligoglycine derivatives, and in a broader definition as N-substituted peptides (peptoid-peptide chimeras). Both types were systematically investigated by force field calculations. The Merck MMFF and YASARA2 force fields were shown to be, among others, the most suitable ones for conformational investigations of peptoids with no missing parameterizations, in contrast to AMBER or CHARMM. Ramachandran-like plots were calculated for dipeptoids and chimeras using energy calculations and grid searches by varying the dihedral angels Φ and Ψ in steps of 10° for s- cis- and s- trans amide bonds. Barriers as well as low energy conformations are compared to peptide Ramachandran plots, showing that peptoids have both, more barriers due to additional steric interactions as well as access to minimum conformations not accessible by peptides. Low energy conformations of dimers were used as starting conformations of higher oligomers of the peptoids for extensive molecular dynamics simulations over 10 or 20 ns with the YASARA2 force field and an explicit water solvent box to evaluate their potential to form secondary structural elements. Especially peptoids with aminoisobutyric acid-like monomer units were found to form left-handed or polyproline-like helices also known from less common natural peptides. Furthermore, new secondary structures appear feasible based on stable conformations outside the allowed areas of the Ramachandran plot for peptides, but allowed for peptoids. © 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 651-668, 2011. [ABSTRACT FROM AUTHOR]

Computer simulation using molecular dynamics is increasingly used to simulate the folding equilibria of peptides and small proteins. Yet, the quality of the obtained results depends largely on the quality of the force field used. This comprises the solute as well as the solvent model and their energetic and entropic compatibility. It is, however, computational very expensive to perform test simulations for each combination of force-field parameters. Here, we use the one-step perturbation technique to predict the change of the free enthalpy of folding of a β-peptide in methanol solution due to changing a variety of force-field parameters. The results show that changing the solute backbone partial charges affects the folding equilibrium, whereas this is relatively insensitive to changes in the force constants of the torsional energy terms of the force field. Extending the cut-off distance for nonbonded interactions beyond 1.4 nm does not affect the folding equilibrium. The same result is found for a change of the reaction-field permittivity for methanol from 17.7 to 30. The results are not sensitive to the criterion, e.g., atom-positional RMSD or number of hydrogen bonds, that is used to distinguish folded and unfolded conformations. Control simulations with perturbed Hamiltonians followed by backward one-step perturbation indicated that quite large perturbations still yield reliable results. Yet, perturbing all solvent molecules showed where the limitations of the one-step perturbation technique are met. The evaluated methodology constitutes an efficient tool in force-field development for molecular simulation by reducing the number of required separate simulations by orders of magnitude. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

On the basis of quantum chemical calculations Cα-glycyl radical parameters have been developed for the OPLS-AA/L force field. The molecular mechanics hypersurface was fitted to the calculated quantum chemical surface by minimizing their molecular mechanics parameter dependent sum-of-squares deviations. To do this, a computer program in which the molecular mechanics energy derivatives with respect to the parameters were calculated analytically was developed, implementing the general method of Lifson and Warshel (J Chem Phys 1968, 49, 5116) for force field parameter optimization. This program, in principle, can determine the optimal parameter set in one calculation if enough representative value points on the quantum chemical potential energy surface are available and there is no linear dependency between the parameters. Some of the parameters in quantum calculations, including several new torsion types around a bond as well as angle parameters at a new central atom type, are not completely separable. Consequently, some restrictions and/or presumptions were necessary during parameter optimization. The relative OPLS-AA energies reproduced those calculated quantum chemically almost perfectly. © 2008 Wiley Periodicals, Inc. J Comput Chem 2008 [ABSTRACT FROM AUTHOR]

A force field for the computer simulation of aqueous solutions of amides is presented. The force field is designed to reproduce the experimentally observed density and Kirkwood–Buff integrals for N-methylacetamide (NMA), allowing for an accurate description of the NMA activity. Other properties such as the translational diffusion constant and heat of mixing are also well reproduced. The force field is then extended to include N,N′-dimethylacetamide and acetamide with good success. Analysis of the simulations of low concentrations of NMA in water indicates a high degree of solvation with only 15% of the NMA molecules involved in solute–solute hydrogen bonding. There is only a weak angular dependence of the solute–solute hydrogen bonding interaction with a minimum at an angle of 65° for the N&bond;H and C&dbond;O dipole vectors. The models presented here provide a basis for an accurate force field for peptides and proteins. © 2006 Wiley Periodicals, Inc. J Comput Chem 27: 1477–1485, 2006 [ABSTRACT FROM AUTHOR]

The ABEEM/MM model (atom-bond electronegativity equalization method fused into molecular mechanics) is applied to study of the polypeptide conformations. The Lennard–Jones and torsional parameters were optimized to be consistent with the ABEEM/MM fluctuating charge electrostatic potential. The hydrogen bond was specially treated with an electrostatic fitting function. Molecular dipole moments, dimerization energies, and hydrogen bond lengths of complexes are reasonably achieved by our model, compared to ab initio results. The ABEEM/MM fluctuating charge model reproduces both the peptide conformational energies and structures with satisfactory accuracy with low computer cost. The transferability is tested by applying the parameters of our model to the tetrapeptide of alanine and another four dipeptides. The overall RMS deviations in conformational energies and key dihedral angles for four di- or tetrapeptide, is 0.39 kcal/mol and 7.7°. The current results agree well with those by the accurate ab initio method, and are comparable to those from the best existing force fields. The results make us believe that our fluctuating charge model can obtain more promising results in protein and macromolecular modeling with good accuracy but less computer cost. © 2005 Wiley Periodicals, Inc. J Comput Chem 27: 1–10, 2006 [ABSTRACT FROM AUTHOR]

We investigate the application of torsion angle molecular dynamics (TAMD) to augment conformational sampling of peptides and proteins. Interesting conformational changes in proteins mainly involve torsional degrees of freedom. Carrying out molecular dynamics in torsion space does not only explicitly sample the most relevant degrees of freedom, but also allows larger integration time steps with elimination of the bond and angle degrees of freedom. However, the covalent geometry needs to be fixed during internal coordinate dynamics, which can introduce severe distortions to the underlying potential surface in the extensively parameterized modern Cartesian-based protein force fields. A “projection” approach (Katritch et al. J Comput Chem 2003, 24, 254–265) is extended to construct an accurate internal coordinate force field (ICFF) from a source Cartesian force field. Torsion crossterm corrections constructed from local molecular fragments, together with softened van der Waals and electrostatic interactions, are used to recover the potential surface and incorporate implicit bond and angle flexibility. MD simulations of dipeptide models demonstrate that full flexibility in both the backbone φ/ψ and side chain χ1 angles are virtually restored. The efficacy of TAMD in enhancing conformational sampling is then further examined by folding simulations of small peptides and refinement experiments of protein NMR structures. The results show that an increase of several fold in conformational sampling efficiency can be reliably achieved. The current study also reveals some complicated intrinsic properties of internal coordinate dynamics, beyond energy conservation, that can limit the maximum size of the integration time step and thus the achievable gain in sampling efficiency. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 1565–1578, 2005 [ABSTRACT FROM AUTHOR]