CHARMM Drude Polarizable Force Field Research Articles

Ion Correlation in Choline Chloride-Urea Deep Eutectic Solvent (Reline) from Polarizable Molecular Dynamics Simulations.

In recent years, deep eutectic solvents (DESs) emerged as highly tunable and environmentally friendly alternatives to common ionic liquids and organic solvents. In this work, a polarizable model based on the CHARMM Drude polarizable force field is developed for a 1:2 ratio mixture of choline chloride/urea (reline) DES. To successfully reproduce the structure of the liquid as compared to first-principles molecular dynamics simulations, a damping factor was introduced to correct the observed over-binding between the chloride and the hydrogen bonding site of choline. Investigated radial distributions reveal the formation of hydrogen bonds between all the constituents of reline and similar interactions for chloride and urea's oxygen atoms, which could contribute to the melting point depression of the mixture. Predicted dynamic properties from our polarizable force field are in good agreement with experiments, showing significant improvements over nonpolarizable models. Similar to some ionic liquids, an oscillatory behavior in the velocity autocorrelation function of the anion is visible, which can be interpreted as a rattling motion of the lighter anion surrounded by the heavier cations. The obtained results for ionic conductivity of reline show some degree of correlated ion motion in this DES. However, a joint diffusion of ion pairs cannot be observed during the simulations.

Testing and Optimizing the Drude Polarizable Force Field for Blocked Amino Acids Based on High-Level Quantum-Mechanical Energy Surfaces

The correct reproduction of conformational substates of amino acids was tested for the CHARMM Drude polarizable force field. This was achieved by evaluating the reorganization energies for all low lying energy minima occurring in all 15 neutral blocked amino acids on a quantum-mechanical (QM) energy surface at the MP2/cc-pVDZ level. The results indicate that the bonded parameters of the N-acetyl (ACE) and N-Methylamide (CT3) blocking groups lead to significant discrepancies. A reparametrization of five bond angles significantly improved the agreement with the QM energy surface. The corrected Drude force field exhibits almost the same average reorganization energies relative to the MP2 energy surface as the AM1 and PM3 semi-empirical methods.

Conformational Flexibilities and Solvation Properties of Insulin in Aromatic Amino Acid Solutions: A Molecular Dynamics Study Using CHARMM Drude Polarizable Model

Aromatic amino acids (AAA) play a crucial role in the structure and function of proteins. A higher level of AAA causes several diseases, controls insulin levels. In this work, we carried out atomistic molecular dynamics simulations by using CHARMM Drude polarizable force field to investigate the conformational properties of insulin monomer in 2M phe, tyr, trp solutions as well as in pure aqueous solution to compare the relative changes of protein conformations, its solvation properties and the interactions of the free AAA with insulin. Although insulin’s native folded form was intact in all the solutions within the simulation length scale, we observed that the protein is a little more flexible and less compact in phe solution than in tyr/trp solutions. The free AAAs identified to self-aggregate around the protein surface and form clusters of different sizes. They interacted with insulin, significantly through cation/anion–π and π–π stacking, and partly through hydrogen bonded interactions. Among the three, trp was prone to interact through cation–π interactions while phe and tyr interacted through π–π stacking with insulin. Despite a significant number of free AAA molecules in the solvation shell, insulin was observed to be sufficiently hydrated and formed hydrogen bonds with water. Some of our findings agreed with the available experimental results that establish the reliability of the chosen force field. Our findings would interpret the interactions between the free AAA and insulin in solution, helpful to recognize the microscopic details of AAA governed biological processes in living organisms.

Deep Learning Based Optimization of Lennard-Jones Parameters for the Drude General Force Field (DGenFF)

The CHARMM Drude polarizable force field (FF) incorporates induced polarization effects in molecular dynamics (MD) simulations based on the classical Drude oscillator model. Implementation of this model improves simulation of electrostatic interactions in MD simulations. The Drude polarizable FF currently extends to proteins, nucleic acids, lipids, carbohydrates; however, it has a limited set of drug-like (organic) molecules. This study focuses on extending CHARMM Drude polarizable FF to a complete set of small molecules to release Drude General Force Field (DGenFF). Parametrization of DGenFF requires introduction of 49 new atom types for a complete expansion comparable to its additive counterpart - CHARMM General Force Field (CGenFF). Introduction of new atom types involves optimization of Lennard-Jones (LJ) parameters targeting model compounds specifically selected for various atom types. The optimization targets experimental thermodynamic properties, like enthalpy of vaporization (ΔHvap) molecular volume (VMol), dielectric constant, and viscosity, among others. To perform LJ parametrization while accounting for correlation and high dimensionality of parameters we harness the predictive ability of Deep Learning (DL) by combining it with an initial design algorithm, Latin Hypercube Design (LHD). LHD extensively explores the multidimensional LJ parameter space for multiple atom types simultaneously to identify a subset of distributed parameter sets. ΔHvap and VMol are then calculated via MD simulations for the LJ parameter sets for selected model compounds creating training for the DL model. The trained DL model then identifies optimal sets of parameters closer to the target experimental data, which are refined and ranked based on QM interactions with rare gases, water and other experimental observables. The developed DL-based parametrization framework represents a high-throughput method of LJ parameter optimization based on experimental and QM properties, whose application to several new atom types will be presented.

Modeling induction phenomena in amino acid cation– $$\pi $$ π interactions

Cation– $$\pi $$ interactions are widely recognized as an important class of interactions, notably in biology and supramolecular chemistry, participating in molecular recognition and association phenomena. Numerical simulations relying on additive force fields perform usually poorly in modeling precisely these interactions. It is now well established that accurate reproduction of the interaction energy of a positively charged group bound to the $$\pi $$ -electron cloud of an aromatic ring requires an explicit treatment of induction effects by means of polarizable potentials. In this contribution, we compare critically the ability of the CHARMM Drude polarizable force field to describe a series of prototypical cation– $$\pi $$ interactions observed in proteins with that of the pairwise additive CHARMM36 force field. Toward this end, potentials of mean force characterizing the binding of amino acid side-chain models, namely ammonium and guanidinium cations, on the one hand, and toluene, para-cresol and 3-methylindole, on the other hand, have been determined within the extended adaptive biasing force framework.

CHARMM Drude Polarizable Force Field for Glycosidic Linkages Involving Pyranoses and Furanoses.

We present an extension of the CHARMM Drude polarizable force field to enable modeling of polysaccharides containing pyranose and furanose monosaccharides. The new force field parameters encompass 1↔2, 1→3, 1→4, and 1→6 pyranose-furanose linkages, 2→1 and 2→6 furanose-furanose linkages, 2→2, 2→3, and 2→4 furanose-pyranose, and 1↔1, 1→2, 1→3, 1→4, and 1→6 pyranose-pyranose linkages. For the glycosidic linkages, both simple model compounds and the full disaccharides with methylation at the reducing end were used for parameter optimization. The model compounds were chosen to be monomers or glycosidic-linked dimers of tetrahydropyran (THP) and tetrahydrofuran (THF). Target data for optimization included one- and two-dimensional potential energy scans of ω and the Φ/Ψ glycosidic dihedral angles in the model compounds and full disaccharides computed by quantum mechanical (QM) RIMP2/cc-pVQZ single point energies on MP2/6-31G(d) optimized structures. Also included in the target data are extensive sets of QM gas phase monohydrate water-saccharide interactions, dipole moments, and molecular polarizabilities for both model compounds and full disaccharides. The resulting polarizable model is shown to be in good agreement with a range of QM data, offering a significant improvement over the additive CHARMM36 carbohydrate force field, as well as experimental data including crystal structures and conformational properties of disaccharides and a trisaccharide in aqueous solution.

Examining the Stability of β-Sheets using the Charmm Drude Polarizable Force Field

β-Sheets are some of the most common secondary structure motifs in proteins, and are important for mediating protein-protein interactions through their association. This association can also lead to the aggregation of misfolded proteins into β-pleated-sheets in neurodegenerative disorders like Alzheimer's disease. Fixed charge, all-atom molecular dynamics simulations have adequately reproduced the folding free energy landscape of a small β-hairpin, the GB1 domain of protein G, which is a prototype for a larger β-pleated-sheet. Polarizable force fields should, in theory, be able to more accurately reproduce experimental results as they are a more realistic model of the molecular system. The CHARMM Drude model is a relatively efficient polarizable force field that has been shown to perform as well or better than traditional non-polarizable force fields in reproducing helical content and folding mechanisms of model α-helical peptides. To assess the model's accuracy for β-sheets, we examined the stability of the GB1 β-hairpin using the CHARMM Drude polarizable force field and two non-polarizable force fields, CHARMM36 and CHARMM22∗. Two-dimensional replica exchange umbrella sampling (REUS) simulations show that the β-hairpin is unstable in the Drude system, whereas it is either stable or quasistable in CHARMM36 and CHARMM22∗, respectively. The instability in Drude appears to be driven mostly by interactions between the peptide backbone and the surrounding water molecules. By tuning these interactions, we have shiftedthe stability back towards the β-hairpin state.

CHARMM Drude Polarizable Force Field for Aldopentofuranoses and Methyl-aldopentofuranosides

An empirical all-atom CHARMM polarizable force filed for aldopentofuranoses and methyl-aldopentofuranosides based on the classical Drude oscillator is presented. A single electrostatic model is developed for eight different diastereoisomers of aldopentofuranoses by optimizing the existing electrostatic and bonded parameters as transferred from ethers, alcohols, and hexopyranoses to reproduce quantum mechanical (QM) dipole moments, furanose-water interaction energies and conformational energies. Optimization of selected electrostatic and dihedral parameters was performed to generate a model for methyl-aldopentofuranosides. Accuracy of the model was tested by reproducing experimental data for crystal intramolecular geometries and lattice unit cell parameters, aqueous phase densities, and ring pucker and exocyclic rotamer populations as obtained from NMR experiments. In most cases the model is found to reproduce both QM data and experimental observables in an excellent manner, whereas for the remainder the level of agreement is in the satisfactory regimen. In aqueous phase simulations the monosaccharides have significantly enhanced dipoles as compared to the gas phase. The final model from this study is transferrable for future studies on carbohydrates and can be used with the existing CHARMM Drude polarizable force field for biomolecules.

CHARMM Drude Polarizable MD Simulations Reproduce Solution X-Ray Diffraction Patterns for B-DNA Sequences and Predict Differential Impact of the Li+, Na+, K+ and Rb+ Ions on DNA Conformational Properties

Recently we have presented the first generation CHARMM Drude polarizable force field for DNA, which is capable of reproducing the main conformational features of DNA in solution, such as A-to-B equilibrium and transitions between BI and BII substates. Our current efforts are directed towards further model improvement, by achieving a proper balance of the interactions among surrounding mobile ions, water and DNA. Compared to the additive (non-polarizable) models, explicit treatment of the electronic polarizability in the Drude model leads to a markedly improved description of the interplay between the ionic atmosphere and DNA conformational behavior. In particular, the Drude model is shown to more accurately reproduce counterion condensation theory predictions of DNA charge neutralization by condensed ions, as well as the experimental data on the competitive binding of Li+, Na+, K+ and Rb+ ions to DNA. The most intriguing results is that the model predicts a differential impact of these seemingly similar monovalent cations on DNA conformational properties - a phenomenon not observed in the state-of-the-art CHARMM36 and AMBER atomistic additive models. In addition, the Drude model reproduces the solution X-ray diffraction patterns for a number of B form DNA sequences at a level of accuracy similar to, or exceeding that of the above mentioned additive models. The obtained results indicate that CHARMM Drude polarizable MD simulations provide a more realistic model of the physical forces involved in the interactions of DNA with its ionic environment, offering the potential to yield new insights into salt-mediated biological processes involving DNA, such as protein-DNA recognition and chromatin folding.

Development of the Charmm Drude Polarizable Force Field for the Study of Ion Interactions in Biological Systems

Ions play several crucial roles in the structure and function of biological systems: maintaining homeostasis, protein activation and stabilization, and cell electrophysiology and signaling. Molecular dynamics simulations are commonly employed to study ion-protein interactions. Since ions frequently have greater charge densities than the surrounding solvent and protein, they induce a dipole on adjacent molecules and moieties. To some degree, this is implicitly modeled within conventional additive atomic charge force fields.

From Small Molecules to Macromolecules: Progress Towards a Charmm Drude Polarizable Force Field for the Nucleic Acids

Electrostatic interactions play a crucial role in determining the structure and function of biomolecules, and an important aspect of the electrostatic interaction is polarizability, the response of the molecular dipoles to an external electric field. Towards development of a comprehensive force field for biomolecules, initial work on the CHARMM Drude polarizable force field for nucleic acids focused on optimizing the theoretical model and developing parameters for small molecule analogs of the sugar, phosphate and base moieties. With parameters for the small molecule analogs now in place, current work is focused on construction of the full nucleic acids, and details of this work will be presented here. Initial simulations of the full nucleic acids have demonstrated that the polarizable model is both robust and stable, and work is now underway to assemble the small molecule building blocks into the full nucleic acids. This procedure requires careful optimization of the parameters associated with covalent connections between the constituent moieties. Following initial optimization of the intramolecular connections, multiple simulations will be performed to provide a detailed assessment of macromolecular properties in comparison to experimental data. These results will be used to identify and correct any weaknesses in the force field, and are also an essential tool for validation of the model in condensed phase environments; they will give new insights into the importance of polarizability in nucleic acid simulations.

Accurate Calculation of Hydration Free Energies using Pair-Specific Lennard-Jones Parameters in the CHARMM Drude Polarizable Force Field.

Lennard-Jones (LJ) parameters for a variety of model compounds have previously been optimized within the CHARMM Drude polarizable force field to reproduce accurately pure liquid phase thermodynamic properties as well as additional target data. While the polarizable force field resulting from this optimization procedure has been shown to satisfactorily reproduce a wide range of experimental reference data across numerous series of small molecules, a slight but systematic overestimate of the hydration free energies has also been noted. Here, the reproduction of experimental hydration free energies is greatly improved by the introduction of pair-specific LJ parameters between solute heavy atoms and water oxygen atoms that override the standard LJ parameters obtained from combining rules. The changes are small and a systematic protocol is developed for the optimization of pair-specific LJ parameters and applied to the development of pair-specific LJ parameters for alkanes, alcohols and ethers. The resulting parameters not only yield hydration free energies in good agreement with experimental values, but also provide a framework upon which other pair-specific LJ parameters can be added as new compounds are parametrized within the CHARMM Drude polarizable force field. Detailed analysis of the contributions to the hydration free energies reveals that the dispersion interaction is the main source of the systematic errors in the hydration free energies. This information suggests that the systematic error may result from problems with the LJ combining rules and is combined with analysis of the pair-specific LJ parameters obtained in this work to identify a preliminary improved combining rule.

Polarizability rescaling and atom-based Thole scaling in the CHARMM Drude polarizable force field for ethers.

Within the CHARMM polarizable force field based on the classical Drude oscillator, atomic polarizabilities are derived via fitting to ab initio calculated data on isolated gas phase molecules, with an empirical scaling factor applied to account for differences between the gas and condensed phases. In the development of polarizable models for the ethers, a polarizability scaling factor of 0.7 was previously applied [Vorobyov et al. J Comput Chem 3:1120-1133, 2007]. While the resulting force field models gave good agreement with a variety of experimental data, they systematically underestimated the liquid phase dielectric constants. Here, a new CHARMM polarizable model is developed for the ethers, employing a polarizability scaling factor of 0.85 and including atom-based Thole scale factors recently introduced into the CHARMM Drude polarizable force field [Harder et al. J Phys Chem B 112:3509-3521, 2008]. The new model offers a significant improvement in the reproduction of liquid phase dielectric constants, while maintaining the good agreement of the previous model with all other experimental and quantum mechanical data, highlighting the sensitivity of liquid phase properties to the choice of atomic polarizability parameters.