Methylguanidinium at the Air/Water Interface: A Simulation Study with the Drude Polarizable Force Field

Zhu, Jian; Huang, Jing

doi:10.1021/acs.jpcb.0c08556

Cited by 6 publications

(4 citation statements)

References 72 publications

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“…Methylguanidinum is one of the better studied amino-acid sidechain analogs, including polarizable FF simulations at an air/water interface 80 and through umbrella sampling membrane permeation studies. 27 In both cases, comparisons were made to a nonpolarizable FF.…”

Section: Resultsmentioning

confidence: 99%

Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer

Montgomery,

Lemkul

2024

Preprint

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The cell membrane functions as a semi-permeable barrier that governs the transport of materials into and out of cells. The bilayer features a distinct dielectric gradient due to the amphiphilic nature of its lipid components. This gradient influences various aspects of small molecule permeation and the folding and functioning of membrane proteins. Here, we employ polarizable molecular dynamics simulations to elucidate the impact of the electronic environment on the permeation process. We simulated eight distinct amino acid sidechain analogs within a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer using the Drude polarizable force field (FF). Our approach including both unbiased and umbrella sampling simulations. By using a polarizable FF, we sought to investigate explicit dipole responses in relation to local electric fields along the membrane normal. We evaluate molecular dipole moments, which exhibit variation based on their localization within the membrane, and compare the outcomes with analogous simulations using the nonpolarizable CHARMM36 FF. This comparative analysis aims to discern characteristic differences in the free energy surfaces of permeation for the various amino acid analogs. Our results provide the first systematic quantification of the impact of employing an explicitly polarizable FF in this context compared to the fixed-charge convention inherent to nonpolarizable FFs, which may not fully capture the influence of the membrane dielectric gradient.

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Section: Resultsmentioning

confidence: 99%

Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer

Montgomery,

Lemkul

2024

Preprint

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show abstract

“…Methylguanidinium is one of the better-studied amino-acid side chain analogs, including polarizable FF simulations at an air/water interface and through umbrella sampling membrane permeation studies . In both cases, comparisons were made to a nonpolarizable FF.…”

Section: Resultsmentioning

confidence: 99%

Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer

Montgomery,

Lemkul

2024

J. Phys. Chem. B

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The cell membrane functions as a semipermeable barrier that governs the transport of materials into and out of cells. The bilayer features a distinct dielectric gradient due to the amphiphilic nature of its lipid components. This gradient influences various aspects of small molecule permeation and the folding and functioning of membrane proteins. Here, we employ polarizable molecular dynamics simulations to elucidate the impact of the electronic environment on the permeation process. We simulated eight distinct amino-acid side chain analogs within a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer using the Drude polarizable force field (FF). Our approach includes both unbiased and umbrella sampling simulations. By using a polarizable FF, we sought to investigate explicit dipole responses in relation to local electric fields along the membrane normal. We evaluate molecular dipole moments, which exhibit variation based on their localization within the membrane, and compare the outcomes with analogous simulations using the nonpolarizable CHARMM36 FF. This comparative analysis aims to discern characteristic differences in the free energy surfaces of permeation for the various amino-acid analogs. Our results provide the first systematic quantification of the impact of employing an explicitly polarizable FF in this context compared to the fixed-charge convention inherent to nonpolarizable FFs, which may not fully capture the influence of the membrane dielectric gradient.

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“…The Drude polarizable force fields have been widely used to understand the peptide folding cooperativity, partitioning of small molecules, , ligand–protein binding dynamics, and interficial properties . A key motivation of this study was to compare simulations with the experimental measurement on the binding free energies between calcium ion and the EF-hand loops.…”

Section: Discussionmentioning

confidence: 99%

“…The Drude polarizable force fields have been widely used to understand the peptide folding cooperativity, 67 partitioning of small molecules, 69 , 70 ligand–protein binding dynamics, 71 and interficial properties. 72 A key motivation of this study was to compare simulations with the experimental measurement on the binding free energies between calcium ion and the EF-hand loops. We first compared the binding energies using the experimentally determined complex structures, and found out that the polarizable Drude-2019 FF reproduced the SAPT calculation results, both in terms of total interaction energies as well as each component of the interaction energies including electrostatic, induction, exchange, and dispersion terms.…”

Section: Discussionmentioning

confidence: 99%

Binding Energy and Free Energy of Calcium Ion to Calmodulin EF-Hands with the Drude Polarizable Force Field

et al. 2021

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Calcium ions are important messenger molecules in cells, which bind calcium-binding proteins to trigger many biochemical processes. We constructed four model systems, each containing one EF-hand loop of calmodulin with one calcium ion bound, and investigated the binding energy and free energy of Ca2+ by the quantum mechanics symmetry-adapted perturbation theory (SAPT) method and the molecular mechanics with the additive CHARMM36m (C36m) and the polarizable Drude force fields (FFs). Our results show that the explicit introduction of polarizability in the Drude not only yields considerably improved agreement with the binding energy calculated from the SAPT method but is also able to capture each component of the binding energies including electrostatic, induction, exchange, and dispersion terms. However, binding free energies computed with the Drude and the C36m FFs both deviated significantly from the experimental measurements. Detailed analysis indicated that one of main reasons might be that the strong interactions between Ca2+ and the side chain nitrogen of Asn/Gln in the Drude FF caused the distorted coordination geometries of calcium. Our work illustrated the importance of polarization in modeling ion–protein interactions and the difficulty in generating accurate and balanced FF models to represent the polarization effects.

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Methylguanidinium at the Air/Water Interface: A Simulation Study with the Drude Polarizable Force Field

Cited by 6 publications

References 72 publications

Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer

Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer

Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer

Binding Energy and Free Energy of Calcium Ion to Calmodulin EF-Hands with the Drude Polarizable Force Field

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