Comparison of two force fields in MD-simulations of α-helical structures in keratins

Molecular dynamic (MD) simulations based on two different force fields, CVFF and CFF91, were carried out in order to check their feasibility for the structural investigation of the wool intermediate filament (IF) monomeric unit. Selecting an ideal α-helix as start conformation, all MD-simulations with CVFF in vaccum show the α-helix to be unstable. Independently of the amino acid sequence of the α-helix, a new helical structure with a larger diameter arises during the MD-simulation, due to a shift of the intrahelical hydrogen bonds. However in simulations with surrounding water the α-helix remains stable throughout the simulations with the CVFF force field. In contrast to this, MD-simulations in vaccume based on the CFF91 force field are able to determine different stabilities for the α-helical start conformation of various IF-segments, that agree well with secondary structure predictions. The simulation results obtained with CFF91 in vacuum can like wise be verified using an explicit water environment. We found that higher partial charges attributed to the atoms of the amide groups that form the intrahelical hydrogen bonds are the reason for the superiority of the CFF91 force field.     

The anharmonic Urey-Bradley force field; the computational algorithm and its application to CF4

In the Urey-Bradley force field, forces between non-bonded atoms are included along with the valence-bond stretching force constants and the valence-angle deformation force constants. The forces between non-bonded atoms are represented by a Lennard-Jones function. The well-known computational difficulties associated with the Urey-Bradley force field, difficulties which compound seriously when one considers the anharmonic terms in the force field, are recognized as a special treatment of a particular redundant coordinate. These computational difficulties are all avoided in the algorithm described in this paper; the redundant coordinates are handled by first transforming the potential-energy function, including linear terms, into Cartesian space. The well-known ‘tree’ redundancy in the six angles about the central carbon atom is also treated properly. Numerical values of the anharmonic normal-coordinate force constants and the anharmonic coefficients are derived.     

Small imines and oximes as model compounds in the optimization of a consistent force field potential energy function

Parameters have been optimized for a potential energy function to be used in molecular mechanics calculations of small imines as a preliminary step to calculations on larger systems. A consistent force field (CFF) program was used, and a new damping algorithm due to Sundius was introduced in the optimization procedure. Optimization of parameters has been done on structural and vibrational data of five small imines and one oxime. The quality of the derived potential energy function is examined by calculations on larger oximes.     

Allinger's gauche hydrogen hypothesis as tested by an alternative force field model

Allinger's hypothesis that gauche hydrogen, rather than gauche methyl interactions are mainly responsible for conformational equilibria was tested by molecular mechanics calculations using the Engler force field model. For the gauche-anti conformational energy of n-butane, effective cancellation among non-bonded in teractions involving the methyl groups results in the gauche hydrogen interactions across the central C-C bond as the single largest contribution to the energy difference. However, the contribution of this interaction is only one third of the 0.9 kcal difference. For 2,3-dimethylbutane, strain analysis of the gauche-anti conformational energy contributions reveals that geminal and gauche CH₃/CH₃ interactions dominate over the gauche hydrogen interaction Similar analyses for several monosubstituted cyclohexanes confirm that “across-the-ring” interactions. between axial substituents and syn -axial hydrogen atoms are still largely responsible for the instability of the axial relative to the equatorial conformer. In disagreement with Allinger's proposal, the “equatorial hydrogen effect” is found to contribute only a minor amount to the conformational energy difference. Allinger's hypothesis is concluded to be force field dependent, and not to have general validity.     

Empirical force field calculations on methylammonium chloride and its deuterated derivatives

A valence force field for the methylammonium ion is presented. The force field was determined from a modified least squares fit of the observed Raman frequencies of methylammonium chloride and three of its deuterated derivatives. In addition, a Urey—Bradley force field was tested; it was found to be impossible to obtain a good fit to the observed frequencies without the inclusion of a non-bonded hydrogen—hydrogen interaction in the potential energy. The reason is that the unmodified Urey—Bradley force field does not include any bend—bend interactions, which are necessary in order to reproduce the rocking modes.     

Modeling of the phase equilibria of polyisobutylene in diisobutylketone with molecular mechanics

A method of calculating interaction parameters used in phase equilibrium calculations has been extended for predicting solvent activities of polymer solutions. A pair of interaction parameters are determined by calculating interaction energies between all pairs of molecules in the solution of interest with a molecular mechanics method known as the consistent force field (CFF). The conformational space of a pair of molecules is sampled with a Monte Carlo algorithm followed by energy minimizations. In this paper, the method is used to calculate interaction parameters and solvent activities for the diisobutylketone/polyisobutylene system, using 2,2,4-trimethylpentane as a model compound for the polymer molecule.     

Free energy perturbation and molecular dynamics calculations of copper binding to azurin

Free energy perturbation/molecular dynamics simulations have been carried out on copper/azurin systems calculating the binding affinities of copper (II) ion to azurin either in the native or in the unfolded state. In order to test the validity of the strategy adopted for the calculations and to establish what force field is suitable for these kinds of calculations, three different force fields, AMBER, CVFF, and CFF, have been alternatively used for the calculations and the results have been compared with experimental data obtained by spectroscopic titrations of copper (II)/azurin solutions and denaturation experiments. Our findings have pointed out that only CFF gives satisfactory results, thus providing a reliable tool for copper binding simulations in copper protein.     

An extended version of boyd''s force field method applicable to heteroatomic molecules Part 3. Glycine, -isoleucine, -norleucine

The force field method developed by Boyd is extended to include molecules containing atoms other than C and H (e.g., N, O, P, S, Cl, Br, …). A new set of force field parameters is determined in order to redefine the potential energy functions that govern the dynamics of the internal (valence coordinates) degrees of freedom of a molecule. It is shown that the minimum of the partial potential energy surface is significantly affected by electrostatic intramolecular interactions. In this regard the non-bonded interactions appear to be less important than the dipole—dipole type interactions for a given interatomic distance when heteroatoms are present in the molecular framework. The reliability of the extended method as regards minimized structure, vibrational spectra and thermodynamic properties has been checked for more than 20 polyatomic molecules. From the correlation between calculated and experimental properties it is concluded that the method has good potential for further applications on polyatomic molecules with increasing size and topological compexities such as adenine and uracil.     

Vapor-liquid equilibria of polymer solutions determined by molecular mechanics

A method of calculating interaction parameters used in phase equilibrium calculations was extended for predicting solvent activities of polymer solutions. A pair of interaction parameters are determined by calculating interaction energies between all pairs of molecules in the solution of interest with a molecular mechanics method called the consistent force field (CFF). The conformational space of a pair of molecules is sampled with a Monte Carlo algorithm followed by energy minimizations. The method is used to calculate solvent activities for the diethylketone/polypropylene system, giving results in good agreement with experimental values. In addition, solvent activities are predicted for the diethylketone/polyethylenesystem for which no experimental data are available. The method is fully predictive, as no fitting to experimental phase-equilibrium data is carried out.     

Influence de la conformation sur le champ de force etles modes de vibration des monohalogénocyclohexanes

Valence force fields and normal modes of vibration of axial and equatorial forms of four monohalogenated cyclohexanes are computed and compared. A new assignment of axial isomers and of the equatorial form of fluorocyclohexane is proposed. Both geometry and force field differences are necessary to explain rotational isomerism splittings. Normal modes of equatorial isomers are rather close to those of cyclohexane. Interactions between non-bonded atoms are found for the axial isomers.     

Conformations of methylcyclooctane. A combined iterative force field—CNDO approach

A combined iterative force field—CNDO molecular orbital approach to conformations of methylcyclooctane is described. This hybrid method involves a full relaxation force-field calculation of conformer structures, followed by a single CNDO calculation on each structure.     

Conformational energies of cyclenes

An universal function for non-bonded interactions, which takes into account the relative orientation of the bonds is considered in calculating the conformational energies of cycloalkenes and cycloalkadienes. A comparison is made with previous results obtained by using usual 6-exp functions for non-bonded interactions.     

Force field for computation of conformational energies,structures, and vibrational frequencies of aromatic polyesters

A CFF93¹ all-atom force field for aromatic polyesters based on ab initio calculations is reported. The force field parameters are derived by fitting to quantum mechanical data which include total energies, first and second derivatives of the total energies, and electrostatic potentials. The valence parameters and the ab initio electrostatic potential (ESP) derived charges are then scaled to correct the systematic errors originating from the truncation of the basis functions and the neglect of electron correlation in the HF/6-31G* calculations. Based on the force field, molecular mechanics calculations are performed for homologues of poly(p-hydroxybenzoic acid) (PHBA) and poly(ethylene terephthalate) (PET). The force field results are compared with available experimental data and the ab initio results. © 1994 by John Wiley & Sons, Inc.     

Model calculations for benzene on Rh(111): a lattice-dynamical approach

A quasi-harmonic lattice-dynamical model has been used to analyze external frequencies for benzene adsorbed on Rh(111). Empirical external force fields which have been derived for a series of other aromatic hydrocarbons are employed for carbon and hydrogen non-bonded interactions, and Xe-Xe functions (and related averages) for the non-bonded interactions of Rh with the benzene molecule. In this way it is possible to choose the most probable among several alternative structures.     

NORMAL VIBRATIONAL ANALYSIS OF CIS-POLYACETYLENE

The normal vibrational calculation was carried out on cis-polyacetylene(PA) and its model compound, cis, trans-2, 4--hexadiene. Based on the observed IR and Raman frequencies, force constants relevant to the cis-structure were refined. Finally a force field common for cis-PA, trans-PA and three model moleculaes was obtained. The observed spectra of cis-PA were theoretically assigned and the similarities and differences between the cis-and trans- conjugate systems were discussed on the basis of normal coordinate calculation.     

Distribution functions in elasticity

The formation of a gel or elastomer entails the linking together of molecules to form a contiguous random network that has macroscopic dimensions. Forces are propagated in networks along polymer chains and through junctions to other chains. It is important to understand the structure of the force constant matrix that describes a system as complicated as this, even in the case where the potential energy is approximated by a simple harmonic function. This force constant matrix was first formulated by James, but because it is a large random matrix, very little progress can be made in the analysis of its properties. We have opted to approach this problem with the use of large scale computations that are based upon simulations of the formation of networks. Subsequent evaluation of the eigenvalue spectrum of the matrix lends considerable insight into the equilibrium and dynamic properties of elastomers. For present purposes this analysis is couched in terms of the calculation of the probability distribution of the gyration tensor for a phantom network in which non-bonded interactions are not considered.     

Molecular mechanics study of transannular amine–ketone (N→C(DOUBLE BOND)O) interaction in medium-sized heterocycles

Medium-sized nitrogen-containing heterocycles have considerable potential as structurally novel templates for new medicinal agents. In order to evaluate this potential and to investigate their binding to various target receptors, satisfactory modeling of the properties of such compounds with force-field based computational methods is required, especially the conformations accessible to the molecules at and around their global minimum conformation. This is currently only possible with selected force fields for compounds that show a special intramolecular interaction such as the transannular interaction between a basic nitrogen atom and a carbonyl carbon atom. This article substantiates this claim and discusses two approaches to modify the commercially available CFF91 force field. The different approaches are discussed and assessed by their performance in reproducing the conformation in the crystal for a series of known model compounds. In summary, very good agreement with the experimental structure is achieved. The modified force fields are then used to investigate a potentially bioactive lead compound. The lead compound is predicted to be able to mimic the shape of a fused-ring compound with biological activity. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1211–1221     

COSMIC(90): An improved molecular mechanics treatment of hydrocarbons and conjugated systems

Summary Four modifications to the COSMIC molecular mechanics force field are described, which greatly increase both its versatility and the accuracy of calculated conformational energies. The Hill non-bonded van der Waals potential function has been replaced by a two-parameter Morse curve and a new H-H potential, similar to that in MM3, incorporated. Hydrocarbon energies in particular are much improved.A simple iterative Hückel pi-electron molecular orbital calculation allows modelling of conjugated systems. Calculated bond lengths and rotational barriers for a series of conjugated hydrocarbons and nitrogen heterocycles are shown to be as accurate as those determined by the MM2 SCF method.Explicit hydrogen-bonding potentials for H-bond acceptor-donor atom pairs have been included to give better hydrogen bond energies and lengths. The van der Waals radii of protonic hydrogens are reduced to 0.5 Å and the energy well depth is increased to 1.0 kcal mol^-1.Two new general atom types, N⁺ _sp ² and O^- _sp ³ , have been introduced which allow a wide variety of charged conjugated systems to be studied. A minimum of parameterisation is required, as the new types are easily included in the Hückel scheme which automatically adjusts bond and torsional parameters according to the defined bond-order relationships.     

Conformational properties of permethylcyclohexane as compared to cyclohexane: A force field study

The conformational properties of the recently synthesized highly strained permethylcyclohexane molecule 2 have been studied by empirical force field calculations using three different potentials (CFF, MM2, MM2′) and second-derivative optimization methods. A comparison of the results with the conformational behavior of parent cyclohexane 1 leads to the following conclusions: The best conformation of 2 is a chair minimum whose six-membered ring is flatter than that of 1 , due to the strong H…H repulsions introduced by the methyl groups. The twist minimum of 2 is energetically less favorable than the chair by an amount similar to 1 . A potential energy barrier Δ V^# for the chair inversion of 2 of 15.32 kcal/mol results with the CFF, only about three kcal/mol higher than for 1 . The free energy of activation ΔG^# for this process obtained with the CFF is 16.96 kcal/mol (at 333 K) and agrees well with the experimental value of 16.7(2) kcal/mol.¹ MM2 and MM2′ give substantially lower and higher potential energy inversion barriers Δ V^# of 9.03 and 20.29 kcal/mol, respectively, which is attributed to inappropriate torsional energy terms in these force fields. The characteristic difference in the conformational behavior of 2 and 1 concerns the boat forms which are substantially less favorable in the per-methyl compound than in 1 . Expectedly, strong H…H repulsions between the 1,4 diaxial flagpole–bowsprit methyl groups in 2 are responsible for this difference. The particularly high strain of the boat forms of 2 leads to flexibility differences as compared to 1 which in turn affect the relative entropies of the various statiomers (stationary point conformations); e.g., the chair ring inversion activation entropies of 2 and 1 are predicted by the CFF calculations to have opposite signs (?4.82 and 3.41 cal/mol K, respectively, at 298 K). The twist and half-twist statiomers of 2 are much more rigid than those of 1 , which is a consequence of the substantially larger boat barriers along their pseudorotational interconversion paths. The boat transition state separating two enantiomeric twist minima represents a barrier calculated to be more than tenfold higher for 2 than for 1 (CFF Δ V^# values 11.14 and 0.92 kcal/mol, respectively); likewise the half-boat chair inversion barrier of 2 is calculated 5.07 kcal/mol less favorable than the respective half-twist barrier. These statiomers are practically equienergetic in the case of 1 . Except for the axial flagpole–bowsprit CH₃ substituents of the boat forms, the methyl groups of all the relevant calculated statiomers of 2 are more or less staggered. The rotational barrier of the equatorial methyl groups of the chair minimum of 2 is computationally predicted to be 5.78 kcal/mol (ΔG^#), i.e., unusually high. Interesting vibrational effects are brought about by the strong H…H repulsions in 2 ; thus the chair minimum has a largest C? H stretching frequency estimated to be 3050 cm^?1 and involves several particularly low frequencies which have a substantial influence on its entropy. CFF calculations for the lower homologue permethylcyclopentane 5 indicate that its pseudorotational properties are similar to those of cyclopentane 4 , in contradistinction to the pair 2/1 .