Comparative Analysis of Protein Hydration from MD simulations with Additive and Polarizable Force Fields

Ngo, Van; Fanning, John Keenan; Noskov, Sergei Y.

doi:10.1002/adts.201800106

Cited by 25 publications

(29 citation statements)

References 82 publications

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“…The slight decrease in the number of water molecules in a single-file wire observed with Drude simulations may be attributed to less favorable water−water interactions but more favorable amide (backbone)−water interactions in the polarizable model, as evident from the hydration free energies obtained from Drude FF and non-polarizable C27 FF. 116,117 Hazel et al 101 argued that, in the folded peptide, hydrogen bonding between backbone amides results in polarization of the CO and N− H bonds; therefore, an induced dipole of an amide plane drives more favorable interactions with water molecules. Their observations can be corroborated from our work by the analysis of the interaction energies (U int ) between the water wire molecules and the coordinating backbone atoms in gA.…”

Section: Resultsmentioning

confidence: 99%

“…This finding emphasizes an importance of careful calibration of ion–water and ion–ligand interactions in model systems such as water, organic mimetics, or model peptides. The challenges in using ion parameters developed to only match aqueous solvation data will become even more critical in cases of ion channels involving cation–carboxylate interactions. , The overbinding of cations to charged protein moieties results in reduced ion diffusion on protein surfaces , and leads to severely underestimated permeabilities, limiting the utility of the existing polarizable force fields in these systems …”

Section: Results and Discussionmentioning

confidence: 99%

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Polarization Effects in Water-Mediated Selective Cation Transport across a Narrow Transmembrane Channel

Ngo

MacKerell

et al. 2021

J. Chem. Theory Comput.

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Despite the progress in modeling complex molecular systems of ever-increasing complexity, a quantitatively accurate computational treatment of ion permeation through narrow membrane channels remains challenging. An important factor to reach this goal is induced electronic polarization, which is likely to impact the permeation rate of small ions through narrow molecular pores. In this work, we extended the recently developed polarizable force field based on the classical Drude oscillators to assess the role of induced polarization effects on the energetics of sodium and potassium ion transport across the gramicidin A (gA) ion channel. The inclusion of induced polarization lowers barriers present in 1D potential of mean force (PMF) for cation permeation by ∼50% compared to those obtained with the additive force field. Conductance properties calculated with 1D PMFs from Drude simulations are in better agreement with experimental results. Polarization of single-file water molecules and protein atoms forming the narrow pore has a direct impact on the free-energy barriers and cation-specific solid-state NMR chemical shifts. Sensitivity analysis indicates that small changes to water–channel interactions can alter the free energy barrier for ion permeation. These results, illustrating polarization effects present in the complex electrostatic environment of the gA channel, have broad implications for revising proposed mechanisms of ion permeation and selectivity in a variety of ion channels.

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Section: Resultsmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Polarization Effects in Water-Mediated Selective Cation Transport across a Narrow Transmembrane Channel

Ngo

MacKerell

et al. 2021

J. Chem. Theory Comput.

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“…We have in the present case used a self-consistent procedure in each time step for the polarizable molecular dynamics, since this allows the use of advanced multi-time-step strategies that significantly reduces the computational cost for a fixed amount of sampling. The charge and Lagrange variables could alternatively be propagated by an extended Lagrange formalism using fictive masses, in analogy with the virtual particles in the Drude model, but this would require the use of significantly smaller time steps …”

Section: Numerical Resultsmentioning

confidence: 99%

“…The charge and Lagrange variables could alternatively be propagated by an extended Lagrange formalism using fictive masses, in analogy with the virtual particles in the Drude model, but this would require the use of significantly smaller time steps. 64 ■ CONCLUSIONS…”

Section: Journal Of Chemical Theory and Computationmentioning

confidence: 99%

Molecular Dynamics Using Nonvariational Polarizable Force Fields: Theory, Periodic Boundary Conditions Implementation, and Application to the Bond Capacity Model

Poier

Lagardère

Piquemal

et al. 2019

J. Chem. Theory Comput.

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We extend the framework for polarizable force fields to include the case where the electrostatic multipoles are not determined by a variational minimization of the electrostatic energy. Such models formally require that the polarization response is calculated for all possible geometrical perturbations in order to obtain the energy gradient required for performing molecular dynamics simulations. By making use of a Lagrange formalism, however, this computationally demanding task can be replaced by solving a single equation similar to that for determining the electrostatic variables themselves. Using the recently proposed bond capacity model that describes molecular polarization at the charge-only level, we show that the energy gradient for nonvariational energy models with periodic boundary conditions can be calculated with a computational effort similar to that for variational polarization models. The possibility of separating the equation for calculating the electrostatic variables from the energy expression depending on these variables without a large computational penalty provides flexibility in the design of new force fields.

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“…While the parameters were shown to provide excellent performance in various reduced models of binding sites, 11,37 their extension to MD simulations of ion-protein interactions and transport in porin proteins elucidated remarkable issues leading to a hindered ion diffusion in the protein interior as well as apparent over-binding to the protein. 38,39 Recently, Villa et al showed, using the Drude FF, that it is possible to capture the complex interaction surface of Mg 2+ with methyl phosphate in the condensed phase, illustrating the feasibility of developing accurate and transferable polarizable potential functions for metal-ligand interactions. 40 However, success in the final deployment of next-generation polarizable FFs depends critically on assessing (i) the vast chemical space presented by the variety of side chains found in proteins and (ii) the strategies for explicitly including charge transfer terms in the case of strongly interacting cations.…”

Section: Introductionmentioning

confidence: 99%

Benchmarking polarizable and non-polarizable force fields for Ca2+–peptides against a comprehensive QM dataset

Amin

Salahub

et al. 2020

The Journal of Chemical Physics

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Explicit description of atomic polarizability is critical for the accurate treatment of inter-molecular interactions by force fields (FFs) in molecular dynamics (MD) simulations aiming to investigate complex electrostatic environments such as metal-binding sites of metalloproteins. Several models exist to describe key monovalent and divalent cations interacting with proteins. Many of these models have been developed from ion-amino-acid interactions and/or aqueous-phase data on cation solvation. The transferability of these models to cation-protein interactions remains uncertain. Herein, we assess the accuracy of existing FFs by their abilities to reproduce hierarchies of thousands of Ca 2+ -dipeptide interaction energies based on density-functional theory calculations. We find that the Drude polarizable FF, prior to any parameterization, better approximates the QM interaction energies than any of the non-polarizable FFs. Nevertheless, it required improvement in order to address polarization catastrophes where, at short Ca 2+ -carboxylate distances, the Drude particle of oxygen overlaps with the divalent cation. To ameliorate this, we identified those conformational properties that produced the poorest prediction of interaction energies to reduce the parameter space for optimization. We then optimized the selected cation-peptide parameters using Boltzmann-weighted fitting and evaluated the resulting parameters in MD simulations of the N-lobe of calmodulin. We also parameterized and evaluated the CTPOL FF, which incorporates charge-transfer and polarization effects in additive FFs. This work shows how QM-driven parameter development, followed by testing in condensed-phase simulations, may yield FFs that can accurately capture the structure and dynamics of ion-protein interactions.

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Comparative Analysis of Protein Hydration from MD simulations with Additive and Polarizable Force Fields

Cited by 25 publications

References 82 publications

Polarization Effects in Water-Mediated Selective Cation Transport across a Narrow Transmembrane Channel

Polarization Effects in Water-Mediated Selective Cation Transport across a Narrow Transmembrane Channel

Molecular Dynamics Using Nonvariational Polarizable Force Fields: Theory, Periodic Boundary Conditions Implementation, and Application to the Bond Capacity Model

Benchmarking polarizable and non-polarizable force fields for Ca2+–peptides against a comprehensive QM dataset

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