Hydration of l-tyrosine in aqueous medium. An experimental and theoretical study by mixed quantum mechanical/molecular mechanics methods

Quantum mechanical/molecular mechanics (QM/MM) calculations were carried out in order to study the theoretical structures of l-tyrosine in both gas phase and in aqueous solution and observe the changes that occur on the structural and vibrational properties in two phases. Therefore, the molecule was characterized by infrared and Raman spectroscopy in solid phase and aqueous solution. Optimized geometries and relative stabilities for the zwitterion l-tyrosine derivatives have been calculated taking into account the solvent effects by using the self-consistent reaction field (SCRF) theory. For a complete assignment of the IR and Raman spectra of l-tyrosine in solid and aqueous solution phases, density functional theory (DFT) calculations were combined with Pulay's scaled quantum mechanical force field (SQMFF) methodology in order to fit the theoretical wavenumber values to the experimental ones. A good agreement between theoretical and available experimental results is found.     

2,6-二巯基嘌呤互变异构体热力学稳定性的密度泛函理论研究

利用密度泛函(DFT)B3LYP/6-311G(d,p)方法,水相计算采用自洽反应场(SCRF)中的Onsager模型,对气相和水相中可能存在的13种2,6-二巯基嘌呤互变异构体进行了全优化,并计算了各异构体的热力学参数、偶极矩及原子净电荷。计算结果表明,不论是气相还是水相,二硫酮DTP(1,3,7)是最稳定的异构体。溶剂化效应使各异构体的稳定性均增强,偶极矩大者其稳定性显著增大。溶剂化吉布斯自由能与异构体在两相中偶极矩之差存在相关性。二硫酮DTP(1,3,7)在水相中与致癌物BPDE进行亲核取代反应时,二硫酮DTP(1,3,7)中的S10原子优先进攻亲电试剂BPDE.     

Conformational dependence of the electrostatic potential-derived charges of dopamine: Ramifications in molecular mechanics force field calculations in the gas phase and in aqueous solution

The electrostatic potential-derived charges for the catecholamine neurotransmitter dopamine were calculated at the STO-3G and 6-31G* basis sets for six different molecular conformations. The degree of variance of the charges with changing conformations was examined. The 6-31G* basis set produced charges that were more sensitive to changes in conformation than those derived from the STO-3G electrostatic potentials. The implication of the charge variations in molecular mechanics calculations was also investigated. The molecular mechanics results in the gas phase exhibited a variance depending upon the charge set used. The force field calculations varied much less when aqueous solvation was included in the calculations through a continuum model. © 1993 John Wiley & Sons, Inc.     

咪唑-1-乙酸:中性分子及两性离子的自洽反应场研究

对咪唑－１－乙酸中性分子和两性离子分别在气相及水溶液中（采用ＳＣＲＦ模型）进行了从头算,探讨了溶剂和基组对体系几何结构和相对稳定性的影响。结果表明,气相中咪唑－１－乙酸主要以中性分子形式出现,而水的强极化作用则导致水溶液中两性离子成为可能的优势结构形式     

A three-point method for evaluations of AMBER force field parameters: an application to copper-based artificial nucleases

We present the theoretical evaluation of new AMBER force field parameters for 12 copper-based nucleases with bis(2-pyridylmethyl) amine, 2,2′-dipyridylamine, imidazole, N,N-bis(2-benzimidazolylmethyl) amine and their derivative ligands based on first-principles electronic structure calculations at the B3LYP level of theory. A three-point approach was developed to accurately and efficiently evaluate the force field parameters for the copper-based nucleases with the ligands. The protocol of RESP atomic charges has been used to calculate the atomic charge distributions of the studied copper-based nucleases. The evaluated force field parameters and RESP atomic charges have been successfully applied in the testing molecular mechanics calculations and molecular dynamics simulations on the nucleases and the nuclease–DNA complexes, respectively. It has been demonstrated that the developed force field parameters and atomic charges can consistently reproduce molecular geometries and conformations in the available X-ray crystal structures and can reasonably predict the interaction properties of the nucleases with DNA. The developed force field parameters in this work provide an extension of the AMBER force field for its application to computational modeling and simulations of the copper-based artificial nucleases associated with DNA.     

Comparison of charge models for fixed-charge force fields: small-molecule hydration free energies in explicit solvent

In molecular simulations with fixed-charge force fields, the choice of partial atomic charges influences numerous computed physical properties, including binding free energies. Many molecular mechanics force fields specify how nonbonded parameters should be determined, but various choices are often available for how these charges are to be determined for arbitrary small molecules. Here, we compute hydration free energies for a set of 44 small, neutral molecules in two different explicit water models (TIP3P and TIP4P-Ew) to examine the influence of charge model on agreement with experiment. Using the AMBER GAFF force field for nonbonded parameters, we test several different methods for obtaining partial atomic charges, including two fast methods exploiting semiempirical quantum calculations and methods deriving charges from the electrostatic potentials computed with several different levels of ab initio quantum calculations with and without a continuum reaction field treatment of solvent. We find that the best charge sets give a root-mean-square error from experiment of roughly 1 kcal/mol. Surprisingly, agreement with experimental hydration free energies does not increase substantially with increasing level of quantum theory, even when the quantum calculations are performed with a reaction field treatment to better model the aqueous phase. We also find that the semiempirical AM1-BCC method for computing charges works almost as well as any of the more computationally expensive ab initio methods and that the root-mean-square error reported here is similar to that for implicit solvent models reported in the literature. Further, we find that the discrepancy with experimental hydration free energies grows substantially with the polarity of the compound, as does its variation across theory levels.     

Calculation of the free energy of solvation for neutral analogs of amino acid side chains

The ability of the GROMOS96 force field to reproduce partition constants between water and two less polar solvents (cyclohexane and chloroform) for analogs of 18 of the 20 naturally occurring amino acids has been investigated. The estimations of the solvation free energies in water, in cyclohexane solution, and chloroform solution are based on thermodynamic integration free energy calculations using molecular dynamics simulations. The calculations show that while the force field reproduces the experimental solvation free energies of nonpolar analogs with reasonable accuracy the solvation free energies of polar analogs in water are systematically overestimated (too positive). The dependence of the calculated free energies on the atomic partial charges was also studied.     

Comparison of implicit solvent models for the simulation of protein-surface interactions

Empirical force field-based molecular simulations can provide valuable atomistic-level insights into protein-surface interactions in aqueous solution. While the implicit treatment of solvation effects is desired as a means of improving simulation efficiency, existing implicit solvent models were primarily developed for the simulation of peptide or protein behavior in solution alone, and thus may not be appropriate for protein interactions with synthetic material surfaces. The objective of this research was to calculate the change in free energy as a function of surface-separation distance for peptide-surface interactions using different empirical force field-based implicit solvation models (ACE, ASP, EEF1, and RDIE with the CHARMM 19 force field), and to compare these results with the same calculations conducted using density functional theory (DFT) combined with the self-consistent reaction field (SCRF) implicit solvation model. These comparisons show that distinctly different types of behavior are predicted with each implicit solvation method, with ACE providing the best overall agreement with DFT/SCRF calculations. These results also identify areas where ACE is in need of improvement for this application and provide a basis for subsequent parameter refinement.     

A molecular mechanics force field for biologically important sterols

A parameterization has been performed of the biologically important sterols cholesterol, ergosterol, and lanosterol for the CHARMM27 all-atom molecular mechanics force field. An automated parameterization method was used that involves fitting the potential to vibrational frequencies and eigenvectors derived from quantum-chemical calculations. The partial charges were derived by fitting point charges to quantum-chemically calculated electrostatic potentials. To model the dynamics of the hydroxyl groups of the sterols correctly, the parameter set was refined to reproduce the energy barrier for the rotation of the hydroxyl group around the carbon connected to the hydroxyl of each sterol. The frequency-matching plots show good agreement between the CHARMM and quantum chemical normal modes. The parameters are tested in a molecular dynamics simulation of the cholesterol crystal structure. The experimental geometry and cell dimensions are well reproduced. The force field derived here is also useful for simulating other sterols such as the phytosterols sigmasterol, and campesterol, and a variety of steroids.     

Ab-initio and density functional study of L- and D-forms of alanine and serine in gas phase and bulk aqueous medium

The molecular geometry of L and D-forms of alanine and serine in gas phase have been studied by using ab-initio quantum chemical calculations at the restricted Hartree-Fock (RHF) level by employing 6-31G and 6-311++G** basis sets. Subsequently, for considering the electron correlations, Density functional Calculations at the Becke3LYP (B3LYP) and Moller-Plesset second order (MP2) level of calculations have been carried out with the same basis sets for these optimized geometries. Effect of solvation in water on the optimized geometries was studied using the polarized continuum model of the self-consistent reaction field (SCRF) theory. The dipole moment, energy, polarizabilities and vibrational frequencies have been calculated in all cases. Frequency analysis was carried out to ensure that optimized geometry corresponds to a total energy minimum.     

CHARMM force field parameters for simulation of reactive intermediates in native and thio-substituted ribozymes

Force field parameters specifically optimized for residues important in the study of RNA catalysis are derived from density-functional calculations, in a fashion consistent with the CHARMM27 all-atom empirical force field. Parameters are presented for residues that model reactive RNA intermediates and transition state analogs, thio-substituted phosphates and phosphoranes, and bound Mg(2+) and di-metal bridge complexes. Target data was generated via density-functional calculations at the B3LYP/6-311++G(3df,2p)// B3LYP/6-31++G(d,p) level. Partial atomic charges were initially derived from CHelpG electrostatic potential fitting and subsequently adjusted to be consistent with the CHARMM27 charges. Lennard-Jones parameters were determined to reproduce interaction energies with water molecules. Bond, angle, and torsion parameters were derived from the density-functional calculations and renormalized to maintain compatibility with the existing CHARMM27 parameters for standard residues. The extension of the CHARMM27 force field parameters for the nonstandard biological residues presented here will have considerable use in simulations of ribozymes, including the study of freeze-trapped catalytic intermediates, metal ion binding and occupation, and thio effects.     

A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6

Successive parameterizations of the GROMOS force field have been used successfully to simulate biomolecular systems over a long period of time. The continuing expansion of computational power with time makes it possible to compute ever more properties for an increasing variety of molecular systems with greater precision. This has led to recurrent parameterizations of the GROMOS force field all aimed at achieving better agreement with experimental data. Here we report the results of the latest, extensive reparameterization of the GROMOS force field. In contrast to the parameterization of other biomolecular force fields, this parameterization of the GROMOS force field is based primarily on reproducing the free enthalpies of hydration and apolar solvation for a range of compounds. This approach was chosen because the relative free enthalpy of solvation between polar and apolar environments is a key property in many biomolecular processes of interest, such as protein folding, biomolecular association, membrane formation, and transport over membranes. The newest parameter sets, 53A5 and 53A6, were optimized by first fitting to reproduce the thermodynamic properties of pure liquids of a range of small polar molecules and the solvation free enthalpies of amino acid analogs in cyclohexane (53A5). The partial charges were then adjusted to reproduce the hydration free enthalpies in water (53A6). Both parameter sets are fully documented, and the differences between these and previous parameter sets are discussed.     

Simulation of phase separation in alcohol/water mixtures using two-body force field and standard molecular dynamics

Standard molecular dynamics simulations have been carried out on pure alcohols and alcohol/water mixtures. A simple atom-atom force field consisting of Lennard-Jones potentials plus coulombic terms over atomic point charges, but without explicit polarization terms, has been specifically fitted to reproduce several experimental properties of the pure alcohols, and has been used for mixtures by developing combination rules with the TIP3P water model. Densities, enthalpies of vaporization, radial distribution functions, self-diffusion coefficients, and rotational correlation functions of the pure alcohols are well reproduced and compare favorably with those from more sophisticated force fields. Some key aspects of the phase behaviour are correctly reproduced by the molecular dynamics simulation, showing a distinct demixing process for the n-butanol/water mixture as opposed to the stability of the t-butanol/water mixtures. The results demonstrate the ability of a molecular dynamics simulation, even in its standard form and with easily accessible time ranges, but with a carefully optimized force field, to simulate and, to a certain extent, predict the properties of binary mixtures.     

Free energies of hydration from thermodynamic integration: Comparison of molecular mechanics force fields and evaluation of calculation accuracy

Four commonly used molecular mechanics force fields, CHARMM22, OPLS, CVFF, and GROMOS87, are compared for their ability to reproduce experimental free energies of hydration (ΔG_hydr) from molecular dynamics (MD) simulations for a set of small nonpolar and polar organic molecules: propane, cyclopropane, dimethylether, and acetone. ΔG_hydr values were calculated by multiconfiguration thermodynamic integration for each of the different force fields with three different sets of partial atomic charges: full charges from an electrostatic potential fit (ESP), and ESP charges scaled by 0.8 and 0.6. All force fields, except for GROMOS87, give reasonable results for ΔG_hydr · if partial atomic charges of appropriate magnitude are assigned. For GROMOS87, the agreement with experiment for hydrocarbons (propane and ethane) was improved considerably by modifying the repulsive part of the carbon-water oxygen Lennard-Jones potential. The small molecules studied are related to the chemical moieties constituting camphor (C₁₀H_l6O). By invoking force-field transferability, we calculated the ΔG_hydr for camphor. With the modified GROMOS force field, a ΔG_hydr within 4 kJ/mol of the experimental value of −14.8 kJ/mol was obtained. Camphor is one of the largest molecules for which an absolute hydration free energy has been calculated by molecular simulation. The accuracy and reliability of the thermodynamic integration calculations were analyzed in detail and we found that, for ΔG_hydr calculations for the set of small molecules in aqueous solution, molecular dynamics simulations of 0.8–1.0 ns in length give an upper statistical error bound of 1.5 kJ/mol, whereas shorter simulations of 0.25 nm in length given an upper statistical error bound of 3.5 kJ/mol. © 1997 by John Wiley & Sons, Inc.     

Post Hartree–Fock and density functional theory studies on Di-Protonated Allopurinol

Post Hartree–Fock and density functional theory (DFT) methods have been employed to study the molecular properties of Di-Protonated Allopurinol²⁺ tautomers in gaseous and aqueous phase environments. The tautomers in gaseous phase have been optimized at MP2/6-311G(2d,2p) and B3LYP/6-311G(2d,2p) levels of theory. The self-consistent reaction field theory (SCRF) has been employed to optimize the tautomers in aqueous phase (ε = 78.5) at B3LYP/6-311G(2d,2p) level of theory and the solvent effect has been studied. The structure, energetics and relative stabilities of the tautomers have been analyzed both in gaseous and aqueous phases. The principle of maximum hardness (MHP) has been tested at B3LYP/6-311G(2d,2p) level of theory. The condensed Fukui functions have been calculated using the atomic charges obtained through Natural population analysis to identify the relative change in the most reactive site of the optimized structures. NMR studies have been carried out, on the basis of Cheeseman coworker’s method, to analyze the molecular environment as well as the delocalization activities of electron clouds.     

Alchemical prediction of hydration free energies for SAMPL

Hydration free energy calculations have become important tests of force fields. Alchemical free energy calculations based on molecular dynamics simulations provide a rigorous way to calculate these free energies for a particular force field, given sufficient sampling. Here, we report results of alchemical hydration free energy calculations for the set of small molecules comprising the 2011 Statistical Assessment of Modeling of Proteins and Ligands challenge. Our calculations are largely based on the Generalized Amber Force Field with several different charge models, and we achieved RMS errors in the 1.4-2.2 kcal/mol range depending on charge model, marginally higher than what we typically observed in previous studies (Mobley et al. in J Phys Chem B 111(9):2242-2254, 2007, J Chem Theory Comput 5(2):350-358, 2009, J Phys Chem B 115:1329-1332, 2011; Nicholls et al. in J Med Chem 51:769-779, 2008; Klimovich and Mobley in J Comput Aided Mol Design 24(4):307-316, 2010). The test set consists of ethane, biphenyl, and a dibenzyl dioxin, as well as a series of chlorinated derivatives of each. We found that, for this set, using high-quality partial charges from MP2/cc-PVTZ SCRF RESP fits provided marginally improved agreement with experiment over using AM1-BCC partial charges as we have more typically done, in keeping with our recent findings (Mobley et al. in J Phys Chem B 115:1329-1332, 2011). Switching to OPLS Lennard-Jones parameters with AM1-BCC charges also improves agreement with experiment. We also find a number of chemical trends within each molecular series which we can explain, but there are also some surprises, including some that are captured by the calculations and some that are not.     

Polarizable and nonpolarizable force fields for alkyl nitrates

Quantum-chemistry-based many-body polarizable and two-body nonpolarizable atomic force fields were developed for alkyl nitrate liquids and pentaerythritol tetranitrate (PETN) crystal. Bonding, bending, and torsional parameters, partial charges, and atomic polarizabilities for the polarizable force field were determined from gas-phase quantum chemistry calculations for alkyl nitrate oligomers and PETN performed at the MP2/aug-cc-pvDz level of theory. Partial charges for the nonpolarizable force field were determined by fitting the dipole moments and electrostatic potential to values for PETN molecules in the crystal phase obtained from molecular dynamics simulations using the polarizable force field. Molecular dynamics simulations of alkyl nitrate liquids and two polymorphs of PETN crystal demonstrate the ability of the quantum-chemistry-based force fields to accurately predict thermophysical and mechanical properties of these materials.     

Problems in molecular dynamics of condensed phases

A review of the recent theoretical and computational activity at the Chemistry Department of the University of Firenze in the field of molecular simulations of condensed phases is reported. The topics considered include quantitative methods for accurate free energy calculations, molecular dynamics of liquids and ionic solutions, chemical reactions in solutions, phase transformations and polymerization reactions at high pressures.     

Conformational simulations of aqueous solvated alpha-conotoxin GI and its single disulfide analogues using a polarizable force field model

The solution conformation of alpha-conotoxin GI and its two single disulfide analogues are simulated using a polarizable force field in combination with the molecular fragmentation quantum chemical calculation. The polarizability is explicitly described by allowing the partial charges and fragment dipole moments to be variables, with values coming from the linear-scaling energy-based molecular fragmentation calculations at the B3LYP/6-31G(d) level. In comparison with the full quantum chemical calculations, the fragmentation approaches can yield precise ground-state energies, dipole moments, and static polarizabilities for peptides. The B3LYP/6-31G(d) charges and fragment-centered dipole moments are introduced in calculations of electrostatic terms in both AmberFF03 and OPLS force fields. Our test calculations on the gas-phase glucagon (PDB code: 1gcn) and solvated alpha-conotoxin GI (PDB code: 1not) demonstrate that the present polarization model is capable of describing the structural properties (such as the relative conformational energies, intramolecular hydrogen bonds, and disulfide bonds) with accuracy comparable to some other polarizable force fields (ABEEM/MM and OPLS-PFF) and the quantum mechanics/molecular mechanics (QM/MM) hybrid model. The employment of fragment-centered dipole moments in calculations of dipole-dipole interactions can save computational time in comparison with those polarization models using atom-centered dipole moments without much loss of accuracy. The molecular dynamics simulations using the polarizable force field demonstrate that two single disulfide GI analogues are more flexible and less structured than the native alpha-conotoxin GI, in agreement with NMR experiments. The polarization effect is important in simulations of the folding/unfolding process of solvated proteins.