Development Of Force Field Parameters Research Articles

Force Fields for High Concentration Aqueous KOH Solutions and Zincate Ions.

Motivated by increasing interest in electrochemical devices that include highly alkaline electrolytes, we investigated two force fields for potassium hydroxide (KOH) at high concentrations in water. The "FNB" model uses the SPC/E water model, while the "FHM" model uses the TIP4P/2005 water model. We also developed parameters to describe zincate ions in these solutions. The density and viscosity of KOH using the FHM model are in better agreement with experiment than the values from the FNB model. Comparing the properties of the zincate solutions to the available experimental data, we find that both force fields agree reasonably well, although the FHM parameters give a better prediction of the viscosity. The developed force field parameters can be used in future simulations of zincate/KOH solutions in combination with other species of interest.

Force field study of catechol dimers and catechol-(H2O)n clusters

Force field parameters were developed for catechol and used to produce optimized structures of catechol dimers and catechol-(H2O)n clusters. The force field optimized structures for the catechol dimer and catechol-(H2O)n (with n = 1 and 2) clusters are benchmarked against quantum chemistry calculations at the B3LYP and w97XD levels of theory; with the quantum chemistry calculations taking into account basis set superposition error. The force field predicts, in agreement with B3LYP and w97XD reasonable structures and relative binding energies for two dimer structures and six catechol-(H2O)n clusters (with n = 1, 2). The developed forcefield parameters are then used to conduct molecular dynamics (MD) simulations for catechol-(H2O)15 cluster to highlight the effect of increased coordination number on the H-bond network around catechol with potential impact on the reactivity of catechol towards ozone in wet conditions. The result of MD simulations suggests that water molecules form a cage of H-bonds network around the hydroxyl groups of catechol, thereby blocking the active sites on catechol.

Development of a Transferable Force Field between Metal-Organic Framework and Its Polymorph.

Conventionally, force fields for specific metal-organic frameworks (MOFs) are derived from quantum chemical simulations, but this method can be computationally intensive, especially in cases for large MOF structures. In this work, we devise a methodology to reduce the force field derivation costs by replacing the original MOF with a smaller polymorphic structure, with the hypothesis that the force field parameters will be transferrable among chemically identical, polymorphic MOF structures. Specifically, we demonstrate this transferability in MOF-177 structure for H2O and NH3 gas molecules and show that the force field parameters derived from a smaller polymorphic MOF-177 can be used accurately to the original MOF-177 structure. This methodology can accelerate the development of force field parameters for large porous materials, in which computational costs for conventional methods are expensive.

Distribution and Transport of CO2 in Hyperbranched Poly(ethylenimine)-Loaded MCM-41: A Molecular Dynamics Simulation Approach.

Fossil fuel use is accelerating climate change, driving the need for efficient CO2 capture technologies. Solid adsorption-based direct air capture (DAC) of CO2 has emerged as a promising mode for CO2 removal from the atmosphere due to its potential for scalability. Sorbents based on porous supports incorporating oligomeric amines in their pore spaces are widely studied. In this study, we investigate the intermolecular interactions and adsorption of CO2 and H2O molecules in hyperbranched poly(ethylenimine) (HB-PEI) functionalized MCM-41 systems to understand the distribution and transport of CO2 and H2O molecules. Density Functional Theory (DFT) is employed to compute the binding energies of CO2 and H2O molecules with HB-PEI and MCM-41 and to develop force field parameters for molecular dynamics (MD) simulations. The MD simulations are performed to examine the distribution and transport of CO2 and H2O molecules as a function of the HB-PEI content. The study finds that an HB-PEI content of approximately 34 wt % is thermodynamically favorable, with an upper limit of HB-PEI loading between 45 and 50 wt %. The distribution of CO2 and H2O molecules is primarily determined by their adsorptive binding energies, for which H2O molecules dominate the occupation of binding sites due to their strong affinity with silanol groups on MCM-41 and amine groups of HB-PEI. The HB-PEI content has a considerable impact on the diffusion of CO2 and H2O molecules. Furthermore, a larger number of water molecules (higher relative humidity) reduces the correlation of CO2 with the MCM-41 pore surface while enhancing the correlation of CO2 with the amine groups of the HB-PEI. Overall, the presence of H2O molecules increases the CO2 correlation with the amine groups and also the CO2 transport within HB-PEI-loaded MCM-41, meaning that the presence of H2O enhances the CO2 capture in the HB-PEI-loaded MCM-41. These findings are consistent with experimental observations of the impact of increasing humidity on CO2 capture while providing new, molecular-level explanations for the macroscopic experimental findings.

Neutron Diffraction with 34S/natS Isotopic Substitution Method on the Solvation Structure of S8 Molecule in Concentrated CS2 Solutions

Abstract Neutron diffraction measurements on 34S/natS isotopically substituted (natS: natural abundance) 6.9 mol% *S8 solutions in CS2 (natural abundance for both S and C atoms) have successfully been carried out in order to examine the possibility of the 34S/natS isotopic difference method neutron diffraction for liquid samples and to obtain novel structural insights into both intramolecular structure and the solvation structure of S8 molecule in concentrated CS2 solutions. Intramolecular structural parameters within the S8 molecule as well as the intermolecular parameters concerning the nearest neighbor *S⋯CS2 interaction have been determined through the least squares fitting analysis of the observed difference interference function, ΔS(Q), which has been derived from the numerical difference between scattering cross sections observed for *S8 with 34S-enriched and natural S solutions in natural CS2. MD simulations were performed with newly developed force field parameters for sulfur atoms in S8 molecule. The results derived by the simulations adequately agree with the neutron experiments.

Development of Force Field Parameters for the Simulation of Single- and Double-Stranded DNA Molecules and DNA-Protein Complexes.

Although molecular dynamics (MD) simulations have been used extensively to study the structural dynamics of proteins, the role of MD simulation in studies of nucleic acid based systems has been more limited. One contributing factor to this disparity is the historically lower level of accuracy of the physical models used in such simulations to describe interactions involving nucleic acids. By modifying nonbonded and torsion parameters of a force field from the Amber family of models, we recently developed force field parameters for RNA that achieve a level of accuracy comparable to that of state-of-the-art protein force fields. Here we report force field parameters for DNA, which we developed by transferring nonbonded parameters from our recently reported RNA force field and making subsequent adjustments to torsion parameters. We have also modified the backbone charges in both the RNA and DNA parameter sets to make the treatment of electrostatics compatible with our recently developed variant of the Amber protein and ion force field. We name the force field resulting from the union of these three parameter sets (the new DNA parameters, the revised RNA parameters, and the existing protein and ion parameters) DES-Amber. Extensive testing of DES-Amber indicates that it can describe the thermal stability and conformational flexibility of single- and double-stranded DNA systems with a level of accuracy comparable to or, especially for disordered systems, exceeding that of state-of-the-art nucleic acid force fields. Finally, we show that, in certain favorable cases, DES-Amber can be used for long-timescale simulations of protein–nucleic acid complexes.

Development and Validation of Fluorinated, Aromatic Amino Acid Parameters for Use with the AMBER ff15ipq Protein Force Field.

We developed force field parameters for fluorinated, aromatic amino acids enabling molecular dynamics (MD) simulations of fluorinated proteins. These parameters are tailored to the AMBER ff15ipq protein force field and enable the modeling of 4, 5, 6, and 7F-tryptophan, 3F- and 3,5F-tyrosine, and 4F- or 4-CF3-phenylalanine. The parameters include 181 unique atomic charges derived using the implicitly polarized charge (IPolQ) scheme in the presence of SPC/Eb explicit water molecules and 9 unique bond, angle, or torsion terms. Our simulations of benchmark peptides and proteins maintain expected conformational propensities on the μs time scale. In addition, we have developed an open-source Python program to calculate fluorine relaxation rates from MD simulations. The extracted relaxation rates from protein simulations are in good agreement with experimental values determined by 19F NMR. Collectively, our results illustrate the power and robustness of the IPolQ lineage of force fields for modeling the structure and dynamics of fluorine-containing proteins at the atomic level.

Development of Force Field Parameters for p-Carborane to Investigate the Structural Influence of Carborane Derivatives on Drug Targets by Complex Formation.

Androgen receptor (AR) has a key role in the development and progression of prostate cancer, and AR antagonists are used for its remedy. Recently, carborane derivatives, which are carbon-containing boron clusters have attracted attention as new AR ligands. Here we determined the force field parameters of 10-vertex and 12-vertex p-carborane to facilitate in silico drug design of boron clusters. Then, molecular dynamics (MD) simulations of complexes of AR-carborane derivatives were performed to evaluate the parameters and investigate the influences of carborane derivatives on the three-dimensional structure of AR. Energy profiles were obtained using quantum chemical calculations, and the force-field parameters were determined by curve fitting of the energy profiles. The results of MD simulations indicated that binding of the antagonist-BA341 changed some hydrogen-bond formations involved in the structure and location of helix 12. Those results were consistent with previously reported data. The determined parameters are also useful for refining the structure of the carborane-receptor complex obtained by docking simulations and development of new ligands with carborane cages not only for AR but also for various receptors.

Development of Cu2+-Based Distance Methods and Force Field Parameters for the Determination of PNA Conformations and Dynamics by EPR and MD Simulations.

Peptide nucleic acids (PNAs) are a promising group of synthetic analogues of DNA and RNA that offer several distinct advantages over the naturally occurring nucleic acids for applications in biosensing, drug delivery, and nanoelectronics. Because of its structural differences from DNA/RNA, methods to analyze and assess the structure, conformations, and dynamics are needed. In this work, we develop synergistic techniques for the study of the PNA conformation. We use CuQ2, a Cu2+ complex with 8-hydroxyquinoline (HQ), as an alternative base pair and as a spin label in electron paramagnetic resonance (EPR) distance methods. We use molecular dynamics (MD) simulations with newly developed force field parameters for the spin labels to interpret the distance constraints determined by EPR. We complement these methods by UV-vis and circular dichroism measurements and assess the efficacy of the Cu2+ label on a PNA duplex whose backbone is based on aminoethylglycine and a duplex with a hydroxymethyl backbone modification. We show that the Cu2+ label functions efficiently within the standard PNA and the hydroxymethyl-modified PNA and that the MD parameters may be used to accurately reproduce our EPR findings. Through the combination of EPR and MD, we gain new insights into the PNA structure and conformations as well as into the mechanism of orientational selectivity in Cu2+ EPR at X-band. These results present for the first time a rigid Cu2+ spin label used for EPR distance measurements in PNA and the accompanying MD force fields for the spin label. Our studies also reveal that the spin labels have a low impact on the structure of the PNA duplexes. The combined MD and EPR approach represents an important new tool for the characterization of the PNA duplex structure and provides valuable information to aid in the rational application of PNA at large.

RNA-Puzzles Round IV: 3D structure predictions of four ribozymes and two aptamers.

RNA-Puzzles is a collective endeavor dedicated to the advancement and improvement of RNA 3D structure prediction. With agreement from crystallographers, the RNA structures are predicted by various groups before the publication of the crystal structures. We now report the prediction of 3D structures for six RNA sequences: four nucleolytic ribozymes and two riboswitches. Systematic protocols for comparing models and crystal structures are described and analyzed. In these six puzzles, we discuss (i) the comparison between the automated web servers and human experts; (ii) the prediction of coaxial stacking; (iii) the prediction of structural details and ligand binding; (iv) the development of novel prediction methods; and (v) the potential improvements to be made. We show that correct prediction of coaxial stacking and tertiary contacts is essential for the prediction of RNA architecture, while ligand binding modes can only be predicted with low resolution and simultaneous prediction of RNA structure with accurate ligand binding still remains out of reach. All the predicted models are available for the future development of force field parameters and the improvement of comparison and assessment tools.

Force Field Parameter Development for the Thiolate/Defective Au(111) Interface.

A molecular-level understanding of the interplay between self-assembled monolayers (SAMs) of thiolates and gold surface is of great importance to a wide range of applications in surface science and nanotechnology. Despite theoretical research progress of the past decade, an atomistic model, capable of describing key features of SAMs at reconstructed gold surfaces, is still missing. In this work, periodic ab initio density functional theory (DFT) calculations were utilized to develop a new atomistic force field model for alkanethiolate (AT) SAMs on a reconstructed Au(111) surface. The new force field parameters were carefully trained to reproduce the key features, including vibrational spectra and torsion energy profiles of ethylthiolate (C2S) in the bridge or staple motif model on the Au(111) surface, wherein, the force constants of the bond and angle terms were trained by matching the vibrational spectra, while the torsion parameters of the dihedral angles were trained via fitting the torsion energy profiles from DFT calculations. To validate the developed force field parameters, we performed classical molecular dynamics (MD) simulations for both pristine and reconstructed Au-S interface models with a (2√3 × 3) unit cell, which includes four dodecanethiolate (C10S) molecules on the Au(111) surface. The simulation results showed that the geometrical features of the investigated Au-S interface models and structural properties of the C10S SAMs are in good agreement with the ab initio MD studies. The newly developed atomistic force field model provides new fundamental insights into AT SAMs on the reconstructed Au(111) surface and adds advancement to the existing interface research knowledge.

Molecular Dynamics Simulations Based on Newly Developed Force Field Parameters for Cu2+ Spin Labels Provide Insights into Double-Histidine-Based Double Electron-Electron Resonance.

Electron paramagnetic resonance (EPR) in combination with the recently developed double-histidine (dHis)-based Cu2+ spin labeling has provided valuable insights into protein structure and conformational dynamics. To relate sparse distance constraints measured by EPR to protein fluctuations in solution, modeling techniques are needed. In this work, we have developed force field parameters for Cu2+-nitrilotriacetic and Cu2+-iminodiacetic acid spin labels. We employed molecular dynamics (MD) simulations to capture the atomic-level details of dHis-labeled protein fluctuations. The interspin distances extracted from 200 ns MD trajectories show good agreement with the experimental results. The MD simulations also illustrate the dramatic rigidity of the Cu2+ labels compared to the standard nitroxide spin label. Further, the relative orientations between spin-labeled sites were measured to provide insight into the use of double electron-electron resonance (DEER) methods for such labels. The relative mean angles, as well as the standard deviations of the relative angles, agree well in general with the spectral simulations published previously. The fluctuations of relative orientations help rationalize why orientation selectivity effects are minimal at X-band frequencies, but observable at the Q-band for such labels. In summary, the results show that by combining the experimental results with MD simulations precise information about protein conformations as well as flexibility can be obtained.

Orientation and dynamics of Cu2+ based DNA labels from force field parameterized MD elucidates the relationship between EPR distance constraints and DNA backbone distances.

Pulsed electron paramagnetic resonance (EPR) based distance measurements using the recently developed Cu2+-DPA label present a promising strategy for measuring DNA backbone distance constraints. Herein we develop force field parameters for Cu2+-DPA in order to understand the features of this label at an atomic level. We perform molecular dynamics (MD) simulations using the force field parameters of Cu2+-DPA on four different DNA duplexes. The distance between the Cu2+ centers, extracted from the 2 μs MD trajectories, agrees well with the experimental distance for all the duplexes. Further analyses of the trajectory provide insight into the orientation of the Cu2+-DPA inside the duplex that leads to such agreement with experiments. The MD results also illustrate the ability of the Cu2+-DPA to report on the DNA backbone distance constraints. Furthermore, measurement of fluctuations of individual residues showed that the flexibility of Cu2+-DPA in a DNA depends on the position of the label in the duplex, and a 2 μs MD simulation is not sufficient to fully capture the experimental distribution in some cases. Finally, the MD trajectories were utilized to understand the key aspects of the double electron electron resonance (DEER) results. The lack of orientational selectivity effects of the Cu2+-DPA at Q-band frequency is rationalized in terms of fluctuations in the Cu2+ coordination environment and rotameric fluctuations of the label linker. Overall, a combination of EPR and MD simulations based on the Cu2+-DPA labelling strategy can contribute towards understanding changes in DNA backbone conformations during protein-DNA interactions.

Frontiers in Modeling Metal–Organic Frameworks

Frontiers in Modeling Metal–Organic Frameworks

Thermal Stability of Peptide Nucleic Acid Complexes.

Peptide nucleic acid (PNA) is a neutral nucleic acid analogue that base pairs with itself and natural nucleic acids. PNA-nucleic acid complexes are more thermally stable than the corresponding complexes of natural nucleic acids. In addition, PNA is biostable and thus used in many antisense and antigene applications to block functional RNA or DNA via sequence-specific interactions. We have recently developed force field parameters for molecular dynamics (MD) simulations of PNA and PNA-involving duplexes with natural nucleic acids. In this work, we provide the first application of this force field to biologically relevant PNA sequences and their complexes with RNA. We investigated thermal stabilities of short PNA-PNA, PNA-RNA, and RNA-RNA duplexes using UV-monitored thermal denaturation experiments and MD simulations at ambient and elevated temperatures. The simulations show a two-state melting transition and reproduce the thermal stability from melting experiments, with PNA-PNA being the most and RNA-RNA the least stable. The PNA-PNA duplex also displays the highest activation energy for melting. The atomistic details of unfolding of PNA duplexes suggest that all PNA-PNA bases melt concomitantly, whereas the RNA-RNA and PNA-RNA are destabilized from the termini toward the central part of the duplexes.

Development of an ATP force field for coarse-grained simulation of ATPases and its application to the maltose transporter.

The biological functions of ATPases, such as myosin, kinesin, and ABC transporter, are due to large conformational motions driven by energy obtained from ATP. Elucidation of the mechanisms underlying these ATP-driven movements is one of the greatest challenges in computational chemistry. It has been shown that the MARTINI coarse-grained method is a promising tool for the investigation of large conformational motions in various proteins. However, this method has not yet been applied to ATPases because of the lack of a force field for the ATP molecule. Here, we developed force field parameters for the ATP molecule and conducted simulations using these parameters for the subunits (MalK2 ) and the full-length structure (MalFGK2 -E) of a maltose transporter. It was found for both targets that the dimerization of the nucleotide binding domains (NBDs) is induced upon ATP binding. Moreover, for the full-length transporter, the conformational transition from the pre-translocation state to the outward-facing state was observed and was accompanied by an initial transport motion of the substrate. It is expected that coarse-grained simulations utilizing the parameters for the ATP molecule developed here will serve as a powerful tool for investigating other ATPases as well. © 2019 Wiley Periodicals, Inc.

Hydration facilitates oxygenation of hemocyanin: perspectives from molecular dynamics simulations.

Molecular dynamics simulations were applied to deoxy- and oxy-hemocyanins using newly developed force field parameters for the dicopper site to evaluate their structural and dynamical properties. Data obtained from the simulations provided information of the oxygenation effect on the active site and overall topology of the protein that was analyzed by root-mean-square deviations, b-factors, and dicopper coordination geometries. Domain I of the protein was found to demonstrate higher flexibility with respect to domain II because of the interfacial rotation between domain I and II that was further endorsed by computing correlative domain movements for both forms of the protein. The oxygenation effect on the overall structure of the protein or polypeptide subunit was further explored via gyration radii evaluated for the metal-binding domain and for the whole subunit. The evaluation of hydration dynamics was carried out to understand the water mediated role of amino acid residues of the solvent tunnel facilitating the entry of oxygen molecule to the dicopper site of hemocyanin.

Force fields for monovalent and divalent metal cations in TIP3P water based on thermodynamic and kinetic properties.

Metal cations are essential in many vital processes. In order to capture the role of different cations in all-atom molecular dynamics simulations of biological processes, an accurate parametrization is crucial. Here, we develop force field parameters for the metal cations Li+, Na+, K+, Cs+, Mg2+, Ca2+, Sr2+, and Ba2+ in combination with the TIP3P water model that is frequently used in biomolecular simulations. In progressing toward improved force fields, the approach presented here is an extension of previous efforts and allows us to simultaneously reproduce thermodynamic and kinetic properties of aqueous solutions. We systematically derive the parameters of the 12-6 Lennard-Jones potential which accurately reproduces the experimental solvation free energy, the activity derivative, and the characteristics of water exchange from the first hydration shell of the metal cations. In order to reproduce all experimental properties, a modification of the Lorentz-Berthelot combination rule is required for Mg2+. Using a balanced set of solution properties, the optimized force field parameters aim to capture the fine differences between distinct metal cations including specific ion binding affinities and the kinetics of cation binding to biologically important anionic groups.

Understanding LuxS-based quorum sensing and its inhibition – molecular dynamics simulation study

Molecular dynamics simulations were successfully applied to LuxS protein and its protein–ligand complex using the newly developed force field parameters for the iron containing active site. To the best of our knowledge, this was the first attempt to develop force field parameters for the iron containing active site of the LuxS protein. From the simulations, catalytically important amino acid residues were identified which were found to stabilise the ligand. Two residues Glu57 and Asp77 were involved in polar interactions while the protein region in the range between amino acid residue 125 and 131 were predicted to facilitate the entry of ligand to the active site. Other residues like Arg65, Asp77, Ile78 and Ser79 were also recognised as ligand stabilising factors deduced from the simulation. These results were also found to be in good agreement with earlier studies and thus demonstrated the successful application of MD simulations to the LuxS protein. Moreover, the simulation data were expected to be considered for the development of rational approaches in order to identify new LuxS-based quorum sensing antagonists for the treatment of pathologies caused by resistant bacteria.

A consistent S-Adenosylmethionine force field improved by dynamic Hirshfeld-I atomic charges for biomolecular simulation.

S-Adenosylmethionine (AdoMet) is involved in many biological processes as cofactor in enzymes transferring its sulfonium methyl group to various substrates. Additionally, it is used as drug and nutritional supplement to reduce the pain in osteoarthritis and against depression. Due to the biological relevance of AdoMet it has been part of various computational simulation studies and will also be in the future. However, to our knowledge no rigorous force field parameter development for its simulation in biological systems has been reported. Here, we use electronic structure calculations combined with molecular dynamics simulations in explicit solvent to develop force field parameters compatible with the AMBER99 force field. Additionally, we propose new dynamic Hirshfeld-I atomic charges which are derived from the polarized electron density of AdoMet in aqueous solution to describe its electrostatic interactions in biological systems. The validation of the force field parameters and the atomic charges is performed against experimental interproton NOE distances of AdoMet in aqueous solution and crystal structures of AdoMet in the cavity of three representative proteins.