Water activity coefficients in aqueous amino acid solutions by molecular dynamics simulation: 1. Force field development

The structural flexibility of DNA plays a key role in many biological processes of DNA, such as protein-DNA interactions, DNA packaging in viruses and nucleosome positioning on genomic DNA. Some experimental techniques have been employed to investigate the structural flexibility of DNA with the combination of elastic models, but these experiments could only provide the macroscopic properties of DNA, and thus, it is still difficult to understand the corresponding microscopic mechanisms. Recently, all-atom molecular dynamics (MD) simulation has emerged as a useful tool to investigate not only the macroscopic properties of DNA, but also the microscopic description of the flexibility of DNA at an atomic level. The most important issue in all-atom MD simulations of DNA is to choose an appropriate force field for simulating DNA. Very recently, a new force field for DNA has been developed based on the last generation force field of Amber bsc0, which was named Amber bsc1. In this work, all-atom MD simulations are employed to study the flexibility of a 30-bp DNA with the force fields of Amber bsc1 and Amber bsc0 in a comparative way. Our aim of the research is to examine the improvement of the new development of force field (Amber bsc1) in the macroscopic and microscopic properties of DNA, in comparison with the corresponding experimental measurements. All the MD simulations are performed with Gromacs 4.6 and lasted with a simulation time of 600 ns. The MD trajectories are analyzed with Curves+ for the last 500 ns, since the system reaches equilibrium approximately after ~100 ns. Our results show that the new force field (Amber bsc1) can lead to the improvements in the macroscopic parameters of DNA flexibility, i.e., stretch modulus S and twist-stretch coupling D become closer to experimental measurements, while bending persistence lengths lp and torsional persistence lengths C from the two force fields (bsc1 and bsc0) are both in good agreement with experimental data. Our microscopic analyses show that the microscopic structure parameters of DNA from the MD simulation with the Amber bsc1 force field are closer to the experimental values than those with the Amber bsc0 force field, except for slide, and the obvious improvements are observed in some microscopic parameters such as twist and inclination. Our further analyses show that the improvements in macroscopic flexibility from the Amber bsc1 force field are tightly related to the microscopic parameters and their fluctuations. This study would be helpful in understanding the performances of Amber bsc1 and bsc0 force fields in the description of DNA flexibility at both macroscopic and microscopic level.

Molecular dynamic (MD) simulations using the BMS nucleic acid force field produce environment and sequence dependent DNA conformations that closely mimic experimentally derived structures. The parameters were initially developed to reproduce the potential energy surface, as defined by quantum mechanics, for a set of small molecules that can be used as the building blocks for nucleic acid macromolecules (dimethyl phosphate, cyclopentane, tetrahydrofuran, etc.). Then the dihedral parameters were fine tuned using a series of condensed phase MD simulations of DNA and RNA (in zero added salt, 4M NaCl, and 75% ethanol solutions). In the tuning process the free energy surface for each dihedral was derived from the MD ensemble and fitted to the conformational distributions and populations observed in 87 A- and B-DNA x-ray and 17 B-DNA NMR structures. Over 41 nanoseconds of MD simulations are presented which demonstrate that the force field is capable of producing stable trajectories, in the correct environments, of A-DNA, double stranded Aform RNA, B-DNA, Z-DNA, and a netropsin-DNA complex that closely reproduce the experimentally determined and/or canonical DNA conformations. Frequently the MD averaged structure is closer to the experimentally determined structure than to the canonical DNA conformation. MD simulations of A- to B- and B- to A-DNA transitions are also shown. A-DNA simulations in a low salt environment cleanly convert into the B-DNA conformation and converge into the RMS space sampled by a low salt simulation of the same sequence starting from B-DNA. In MD simulations using the BMS force field the B-form of d(GGGCCC)2 in a 75% ethanol solution converts into the A-form. Using the same methodology, parameters, and conditions the A-form of d(AAATTT)2 correctly converts into the B- DNA conformation. These studies demonstrate that the force field is capable of reproducing both environment and sequence dependent DNA structures. The 41 nanoseconds (nsec) of MD simulations presented in this paper paint a global picture which suggests that the DNA structures observed in low salt solutions are largely due to the favorable internal energy brought about by the nearly uniform screening of the DNA electrostatics. While the conformations sampled in high salt or mixed solvent environments occur from selective and asymmetric screening of the phosphate groups and DNA grooves, respectively, brought about by sequence induced ion and solvent packing.

<p>The use of computational simulation to study the dynamics and interactions of macromolecules has become an important tool in the field of biochemistry. A common method to perform these simulations is to use all-atom explicit-solvent molecular dynamics (MD). However, due to the limitations in computational power currently available, this method is not practical for simulating large-scale biomolecular systems on long timescales. An alternative is to perform implicit-solvent Brownian dynamics (BD) simulations using a coarse grained (CG) model that allows for increased computational efficiency. However, if simulations using the CG model are not realistic, then the gain in computational efficiency from using a CG model is not worthwhile.</p> <p>This thesis describes the derivation of a set of bonded and nonbonded CG potential functions for use in implicit-solvent BD simulations of proteins derived from all-atom explicit-solvent MD simulations of amino acids. To determine which force field and water model to use in the MD simulations, Chapter II describes 1 Μs all-atom explicit-solvent MD simulations of glycine, asparagine, phenylalanine, and valine solutions at 50, 100, 200 and 300 mg/ml concentrations performed using eight different force field and water model combinations. To evaluate the accuracy of the force fields at high solute concentrations, the density, viscosity, and dielectric increments of the four amino acids were calculated from the simulations and compared to experimental results. Additionally, the change in the strength of hydrophobic and electrostatic interactions with increasing solute concentration was calculated for each force field and water model combination. As a result of this study, the Amber ff99SB-ILDN force field and TIP4P-Ew explicit-solvent water model were chosen for all subsequent MD simulations. Chapter III describes the derivation of CG bonded potential functions from 1 Μs all-atom explicit-solvent MD simulations of each of the twenty amino acids, including a separate simulation for protonated histidine. The angle and dihedral probability distributions sampled during the MD simulations were used to optimize the bonded potential functions using the iterative Boltzmann inversion (IBI) method. Chapter IV describes the derivation of CG nonbonded potential functions from 1 Μs all-atom explicit-solvent MD simulations of every possible pairing of the amino acids (231 different systems). The radial distribution functions calculated from these MD simulations were used to optimize a set of nonbonded CG potential functions using the IBI method. The optimized set of bonded and nonbonded potential functions, which is termed COFFDROP (COarse-grained Force Field for Dynamic Representation Of Proteins), quantitatively reproduced all of the calculated MD distributions. To determine if COFFDROP would be useful for simulations of bimolecular systems, Chapter V describes the testing of the transferability of the force field. First, COFFDROP was used to simulate concentrated amino acid solutions. The clustering of the solutes in these simulations was directly compared with results from corresponding all-atom explicit-solvent MD simulations and found to be in excellent agreement. Next, BD simulations of 9.2 mM solutions of the small protein villin headpiece were performed. The proteins aggregated during these simulations, which is in agreement with results from MD simulation but in disagreement with experiment. After scaling the strength of COFFDROP's nonbonded potential functions by a factor of 0.8 and rerunning the BD simulations, the amount of aggregation was comparable to experimental observations. Based on these results, COFFDROP is likely to be applicable in CG BD simulations of large, highly concentrated, biomolecular systems.</p>

Molecular dynamics (MD) simulations are extensively used in the study of the structures and functions of proteins. Ab initio protein structure prediction is one of the most important subjects in computational biology, and many trials have been performed using MD simulation so far. Since the results of MD simulations largely depend on the force field, reliable force field parameters are indispensable for the success of MD simulation. In this work, we have modified atom charges in a standard force field on the basis of water-phase quantum chemical calculations. The modified force field turned out appropriate for ab initio protein structure prediction by the MD simulation with the generalized Born method. Detailed analysis was performed in terms of the conformational stability of amino acid residues, the stability of secondary structure of proteins, and the accuracy for prediction of protein tertiary structure, comparing the modified force field with a standard one. The energy balance between alpha-helix and beta-sheet structures was significantly improved by the modification of charge parameters.

The applicability of molecular dynamics simulations for studies of protein folding or intrinsically disordered proteins critically depends on quality of energetic functions-force fields. The four popular force fields for biomolecular simulations, CHARMM22/CMAP, AMBER FF03, AMBER FF99SB, and OPLS-AA/L, were compared in prediction of conformational propensities of all common proteinogenic amino acids. The minimalistic model of terminally block amino acids (dipeptides) was chosen for assessment of side chain effects on backbone propensities. The precise metadynamics simulations revealed striking inconsistency of trends in conformational preferences as manifested by investigated force fields for both backbone and side chains. To trace this disapproval between force fields, the two related AMBER force fields were studied more closely. In the cases of FF99SB and FF03, we uncovered that the distinct tends were driven by different charge models. Additionally, the effects of recent correction for side chain torsion (FF99SB-ILDN) were examined on affected amino acids and exposed significant coupling between free energy profiles and propensities of backbone and side chain conformers. These findings have important consequences for further force field development.

Molecular dynamics (MD) simulations have been widely applied to computer-aided drug design (CADD). While MD has been used in a variety of applications such as free energy perturbation and long-time simulations, the accuracy of the results from those methods depends strongly on the force field used. Force fields for small molecules are crucial, as they not only serve as building blocks for developing force fields for larger biomolecules but also act as model compounds that will be transferred to ligands used in CADD. Currently, a wide range of small molecule force fields based on additive or nonpolarizable models have been developed. While these nonpolarizable force fields can produce reasonable estimations of physical properties and have shown success in a variety of systems, there is still room for improvements due to inherent limitations in these models including the lack of an electronic polarization response. For this reason, incorporating polarization effects into the energy function underlying a force field is believed to be an important step forward, giving rise to the development of polarizable force fields. Recent simulations of biological systems have indicated that polarizable force fields are able to provide a better physical representation of intermolecular interactions and, in many cases, better agreement with experimental properties than nonpolarizable, additive force fields. Therefore, this chapter focuses on the development of small molecule force fields with emphasis on polarizable models. It begins with a brief introduction on the importance of small molecule force fields and their evolution from additive to polarizable force fields. Emphasis is placed on the additive CHARMM General Force Field and the polarizable force field based on the classical Drude oscillator. The theory for the Drude polarizable force field and results for small molecules are presented showing their improvements over the additive model. The potential importance of polarization for their application in a wide range of biological systems including CADD is then discussed.

Molecular dynamics (MD) simulations of six upgraded empirical force fields were compared and evaluated with short peptides, intrinsically disordered proteins, and folded proteins using trajectories of 1, 1.5, 5, or 10 μs (five replicates of 200 ns, 300 ns, 1 μs, or 2 μs) for each system. Previous studies have shown that different force fields, water models, simulation methods, and parameters can affect simulation outcomes. Here, the MD simulations were done in an explicit solvent with RS-peptide, HEWL19, HIV-rev, β amyloid (Aβ)-40, Aβ-42, phosphodiesterase-γ, CspTm, and ubiquitin using ff99IDPs, ff14IDPs, ff14IDPSFF, ff03w, CHARMM36m, and CHARMM22* force fields. The IDP ensembles generated by six all-atom empirical force fields were compared against NMR data. Despite using identical starting structures and simulation parameters, ensembles obtained with different force fields exhibit significant differences in NMR RMDs, secondary structure contents, and global properties such as the radius of gyration. The intrinsically disordered protein (IDP)-specific force fields could substantially reproduce the experimental observables in force field comparison: they have the lowest error in chemical shifts and J-couplings for short peptides/proteins, reasonably well for large IDPs and reasonably well with the radius of gyration. A high population of disorderness was observed in the IDP-specific force field for the IDP ensemble with a fraction of β sheets for β-amyloids. CHARMM22* performs better for many observables; however, it still has a preference toward the helicity for short peptides. The results of β-amyloid 42 starting from two different initial structures (Aβ421Z0Q and Aβ42model) were also compared with DSSP and NMR data. The results obtained with IDP-specific force fields within 2 μs simulation time are similar, even though starting from different structures. The current force fields perform equally well for folded proteins. The results of currently developed or modified force fields for IDPs are capable of enlightening the overall performance of the force field for disordered as well as folded proteins, thereby contributing to force field development.

Artemisinin is widely employed to treat malaria. A variety of experiments have been done to research the dissolution property of artemisinin in different solvents. To have an in-depth understanding of the property, it is essential to explore the dissolution property from molecular level with molecular dynamics (MD) simulation, which needs a satisfactory force field of artemisinin. Therefore in the research a quantum chemistry based force field was developed. The quantum chemical calculation at different levels was done and Hartree–Fock (HF) level calculation gives satisfactory results. The charge distribution was then determined successfully. The van der Waals (VDW) parameters of the C unit with sp3-C were tuned according to the difference between the dissolution enthalpy of artemisinin in ethanol and ethyl acetate. With the developed force field, MD method was employed to successfully simulate the dissolution property of artemisinin in different solvents. The simulation results show that artemisinin molecules tends to aggregate in water, while in the aqueous solution of ethanol, the same number of artemisinin molecules tends to disperse. Furthermore, simulation results show that 8 M ethyl acetate aqueous solution has better dissolution ability than 8 M ethanol aqueous. The simulation gave agreements with the experimental results.

The adsorption mechanism of water on the GaN (0001) polar surface is investigated via both the Density Functional Theory (DFT) method and its derived classical force field. The physisorption binding energy and the adsorption geometry of the water molecule on the clean Ga-terminated surface are analyzed via the first-principle static calculations. The adsorption energy hypersurfaces are then extracted to be used in the fitting of the interaction potentials between water and GaN. Classical molecular dynamics (MD) simulations based on the developed force field are performed for the interfacial system of liquid water and the GaN surface slab. From our computations, the interfacial water exhibits significant oscillatory profiles for the atomic densities and the molecular orientations. Further data analysis suggests a highly confined first layer with the O being locked right upon the surface Ga atoms and the H pointing toward the neighboring O to form the weakened hydrogen bonds. A bilayer configuration with opposite dipole orientations is consequently characterized as the wetting structure on the GaN polar surface and is explained by the anisotropic perturbations from the surface polar sites. Our simulations would be helpful to provide an atomistic picture for the water adsorption configuration on this semiconductor surface and would be useful in the relevant nanofluidic and nanoengineering applications.

Structure and dynamics are both critical to RNA’s vital functions in biology. Numerous techniques can elucidate the structural dynamics of RNA, but computational approaches based on experimental data arguably hold the promise of providing the most detail. In this Account, we highlight areas wherein molecular dynamics (MD) and quantum mechanical (QM) techniques are applied to RNA, particularly in relation to complementary experimental studies.We have expanded on atomic-resolution crystal structures of RNAs in functionally relevant states by applying explicit solvent MD simulations to explore their dynamics and conformational changes on the submicrosecond time scale. MD relies on simplified atomistic, pairwise additive interaction potentials (force fields). Because of limited sampling, due to the finite accessible simulation time scale and the approximated force field, high-quality starting structures are required.Despite their imperfection, we find that currently available force fields empower MD to provide meaningful and predictive information on RNA dynamics around a crystallographically defined energy minimum. The performance of force fields can be estimated by precise QM calculations on small model systems. Such calculations agree reasonably well with the Cornell et al. AMBER force field, particularly for stacking and hydrogen-bonding interactions. A final verification of any force field is accomplished by simulations of complex nucleic acid structures.The performance of the Cornell et al. AMBER force field generally corresponds well with and augments experimental data, but one notable exception could be the capping loops of double-helical stems. In addition, the performance of pairwise additive force fields is obviously unsatisfactory for inclusion of divalent cations, because their interactions lead to major polarization and charge-transfer effects neglected by the force field. Neglect of polarization also limits, albeit to a lesser extent, the description accuracy of other contributions, such as interactions with monovalent ions, conformational flexibility of the anionic sugar−phosphate backbone, hydrogen bonding, and solute polarization by solvent. Still, despite limitations, MD simulations are a valid tool for analyzing the structural dynamics of existing experimental structures. Careful analysis of MD simulations can identify problematic aspects of an experimental RNA structure, unveil structural characteristics masked by experimental constraints, reveal functionally significant stochastic fluctuations, evaluate the structural role of base ionization, and predict structurally and potentially functionally important details of the solvent behavior, including the presence of tightly bound water molecules. Moreover, combining classical MD simulations with QM calculations in hybrid QM/MM approaches helps in the assessment of the plausibility of chemical mechanisms of catalytic RNAs (ribozymes).In contrast, the reliable prediction of structure from sequence information is beyond the applicability of MD tools. The ultimate utility of computational studies in understanding RNA function thus requires that the results are neither blindly accepted nor flatly rejected, but rather considered in the context of all available experimental data, with great care given to assessing limitations through the available starting structures, force field approximations, and sampling limitations. The examples given in this Account showcase how the judicious use of basic MD simulations has already served as a powerful tool to help evaluate the role of structural dynamics in biological function of RNA.

Membrane permeability of cyclic peptides is an important factor in drug design. To investigate the membrane permeability of cyclic peptides using molecular dynamics (MD) simulations, the accurate force fields for unnatural amino acids present in the cyclic peptides are required. Therefore, we developed the CHARMM force fields of the unnatural amino acids present in cyclosporin A (CsA), a cyclic peptide used as an immune suppressor. Especially for N-methyl amino acids, which contribute to the membrane permeability of cyclic peptides, we developed a grid correction map (CMAP) of the energy surface using the φ and ψ dihedral angles in the main chain of CsA. To validate the developed force field, we performed MD simulations, including the generalized replica exchange with solute tempering method, of CsA in water and chloroform solvents. The conformations of CsA in water and chloroform sampled using the developed force field were consistent with those of the experimental results of the solution nuclear magnetic resonance spectroscopy.

The role of ribonucleic acid (RNA) in biology continues to grow, but insight into important aspects of RNA behavior is lacking, such as dynamic structural ensembles in different environments, how flexibility is coupled to function, and how function might be modulated by small molecule binding. In the case of proteins, much progress in these areas has been made by complementing experiments with atomistic simulations, but RNA simulation methods and force fields are less mature. It remains challenging to generate stable RNA simulations, even for small systems where well-defined, thermostable structures have been established by experiments. Many different aspects of RNA energetics have been adjusted in force fields, seeking improvements that are transferable across a variety of RNA structural motifs. In this work, the role of weak CH···O interactions is explored, which are ubiquitous in RNA structure but have received less attention in RNA force field development. By comparing data extracted from high-resolution RNA crystal structures to energy profiles from quantum mechanics and force field calculations, it is shown that CH···O interactions are overly repulsive in the widely used Amber RNA force fields. A simple, targeted adjustment of CH···O repulsion that leaves the remainder of the force field unchanged was developed. Then, the standard and modified force fields were tested using molecular dynamics (MD) simulations with explicit water and salt, amassing over 300 μs of data for multiple RNA systems containing important features such as the presence of loops, base stacking interactions as well as canonical and noncanonical base pairing. In this work and others, standard force fields lead to reproducible unfolding of the NMR-based structures. Including a targeted CH···O adjustment in an otherwise identical protocol dramatically improves the outcome, leading to stable simulations for all RNA systems tested.

Molecular dynamics (MD) simulations based on atomic models play an important role in the drug-discovery process to screen molecules, estimate binding free energies, and optimize lead compounds in chemical space. Accurate computations of thermodynamic and kinetic properties using MD simulations are highly dependent on the accuracy of the underlying atomic force field. In this context, going beyond the nonpolarizable fixed-charge model by accounting explicitly for induced polarization is highly desirable. The CHARMM polarizable force field based on classical Drude oscillators, in which an auxiliary charged particle is attached via a harmonic spring to its parent nucleus, offers both a computationally convenient and rigorous framework to model explicitly induced electronic polarization in MD simulations. For any molecule of interest, electrostatic partial charges, atomic polarizabilities, and Thole shielding factors, as well as bonded parameters can either be determined from ab initio calculations or ascribed from the knowledge-based library of the CHARMM Generalized force field. While this approach is fairly reliable in general, it is well understood that the overall accuracy of the models with respect to thermodynamic properties such as bulk density, enthalpies, and solvation free energies is particularly sensitive to the nonbonded Lennard-Jones (LJ) parameters. In the present study, we systematically refined the set of LJ parameters for the atom types available in the Drude force field to best match the experimental thermodynamic properties for 416 small druglike organic molecules. To further test the transferability of the optimized parameters, the hydration free energy of 372 molecules was computed. The calculations resulted in a small average error of 0.46 kcal/mol and a Pearson R of 0.9, representing a significant improvement over the additive GAFF force field in our previous study, where an average error of ∼2 kcal/mol was obtained. Such an improvement is consistent with the ability of the polarizable Drude model to more accurately model interactions in different environments. The effort provides a roadmap for the global optimization of force field parameters using experimental data. It is hoped that the present effort will further the application of the Drude polarizable force field in molecular simulations including drug design and discovery.

MDWiZ: A platform for the automated translation of molecular dynamics simulations

RNA polymerase II (Pol II) forms a complex with elongation factors to proceed to the elongation stage of the transcription process. In this work, we studied the elongation factor SPT5 and explored the protein-nucleic acid interactions for the isolated systems of KOW1 and KOW4 domains of SPT5 with DNA and RNA, respectively. We performed molecular dynamics (MD) simulations using three commonly used force fields that are CHARMM c36m, AMBER ff14sb, and ff19sb. Simulations showed strong protein-nucleic acid interactions and low electrostatic binding free energies for all force fields used. RNA was found to be highly dynamic with all force fields, while DNA had relatively more stable conformations with the AMBER force fields compared to that with CHARMM. Furthermore, we performed MD simulations of the complete elongation complex using CHARMM c36m and AMBER ff19sb force fields to compare the dynamics and interactions with the isolated systems. Similarly, strong KOW1 and DNA interactions were observed in the complete elongation complex simulations and DNA was further stabilized by a network of interactions involving SPT5-KOW1, SPT4, and rpb2 of Pol II. Overall, our study showed that the differences between CHARMM and AMBER force fields strongly affect the dynamics of the nucleic acids. CHARMM provides highly flexible DNA, while AMBER largely stabilizes the DNA structure. Although the presence of the entire interaction network stabilized the DNA and decreased the differences in the results from the two force fields, the discrepancies of the force fields for smaller systems may reflect their problems in generating accurate dynamics of nucleic acids.