Automation of the Charmm General Force Field for Drug-Like Molecules

Vanommeslaeghe, Kenno; Ghosh, Jayeeta; Polani, Narendra K.; Sheetz, Michael P.; Pamidighantam, Sudhakar; Connolly, John; MacKerell, Alexander D.

doi:10.1016/j.bpj.2010.12.3519

Cited by 17 publications

(14 citation statements)

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“…The molecular dynamic simulations were performed with gromacs5 packages (Abraham et al, 2015), with the charmm36 force field (Klauda et al, 2010) and the TIP3P water model (Jorgensen, Chandrasekhar, Madura, Impey, & Klein, 1983) used. The topology files, charges, and force field parameters of RIV were generated by online software charmm General Force Field (CGenFF; Vanommeslaeghe, Raman, & Mackerell, 2012;Vanommeslaeghe et al, 2009Vanommeslaeghe et al, , 2011. Each system was put in a SPC216 water box (Berendsen, Postma, van Gunsteren, & Hermans, 1981) where the distance from the edge of the box to the surface of the complex was at least 1 nm.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

An unexpected dynamic binding mode between coagulation factor X and Rivaroxaban reveals importance of flexibility in drug binding

et al. 2019

Chem Biol Drug Des

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Rivaroxaban (RIV) is a direct oral anticoagulant (DOAC) targeting activated coagulation factor X (FXa). An earlier study reported the F174A mutant of FXa resistant to a RIV‐like inhibitor, Apixaban. In current study, the detailed molecular mechanism of the resistance has been explored by molecular dynamics simulations on the impaired interactions between RIV and FXa in the damaged S4 pocket of F174A mutant. Besides, an unexpected relative stable binding mode of S1′S1 was revealed, which required dynamic motions of Gln192 and Gln61 to allow the morpholinone moiety of RIV to shift into the S1′ pocket and form strong interactions. These dynamic motions of RIV and critical residues might be important in drug design for direct inhibitors of coagulation factors.

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Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

An unexpected dynamic binding mode between coagulation factor X and Rivaroxaban reveals importance of flexibility in drug binding

et al. 2019

Chem Biol Drug Des

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“…To create the EGCG topology the CHARMM general force field (CGenFF) [33][34][35][36] for organic molecules (program version 0.9.1 beta) was used and translated into GROMACS topology format using in-house code. A coiled-coil keratin fragment was modeled based on the Cortexillin I domain (Protein Data Bank entry: 1D7M).…”

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confidence: 99%

Molecular and thermodynamic basis for EGCG‐Keratin interaction‐part I: Molecular dynamics simulations

et al. 2013

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Nonspecific binding of small molecules to proteins influences transdermal permeation and intestinal absorption, yet understanding of the molecular and thermodynamic basis is still limited. In this study, we report all-atom, fully solvated molecular dynamics simulations of the thermodynamic characteristics of epigallocatechin-3-gallate (EGCG) binding keratin. Experimental validation is reported in Part II. Herein, 18 μs of simulation sampling was calculated. We show that the binding process is a combination of hydrophobic interaction, hydrogen bonding and aromatic interaction. The umbrella sampling technique was used to calculate the binding free energy of EGCG with keratin segments. By extracting EGCG from the keratin-EGCG complex using steered molecular dynamics, the rupture force was observed to be linearly related to the binding free energy. Multilayer binding of EGCG clusters to keratin has been shown. The binding free energy of -6.2 kcal mol obtained from the simulations was in excellent agreement with the experimental Part II. © 2013 American Institute of Chemical Engineers

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“…42 CGENFF topologies and parameters 43 for the three inhibitors were generated using Paramchem. [44][45] To match the experimental conditions, tris(hydroxymethyl)aminomethane and chloride ions were added to make 50 mM Tris solutions. To ensure an overall charge of zero in the system, additional counter-ions were added.…”

Section: Experimental Binding Datamentioning

confidence: 99%

An Approach to Alchemical Binding Free-Energy Calculations Using Coupled Topologies

Huggins

2018

Preprint

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<p>We present an approach to performing alchemical binding free energies which we term coupled topologies. Simultaneously coupling a molecule in the bound state while decoupling it in the unbound state allows us to calculate free energy changes where the system changes charge, without the need to correct for simulation artifacts. This solves a longstanding problem in computing free energy changes. The approach is applied to separated topology relative binding free energy calculations, but is appropriate for single topology calculations and dual topology calculations as well as absolute binding free energy calculations. We apply the method to small-molecule inhibitors of AmpC β-lactamase and show the coupled topologies approach yields results that are in excellent agreement with experiment and good agreement with a state-of-the-art separated topology approach. The promising results on this test case suggest that the coupled topologies approach will be a useful addition to the available arsenal of free-energy methods.</p>

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Automation of the Charmm General Force Field for Drug-Like Molecules

Cited by 17 publications

References 0 publications

An unexpected dynamic binding mode between coagulation factor X and Rivaroxaban reveals importance of flexibility in drug binding

An unexpected dynamic binding mode between coagulation factor X and Rivaroxaban reveals importance of flexibility in drug binding

Molecular and thermodynamic basis for EGCG‐Keratin interaction‐part I: Molecular dynamics simulations

An Approach to Alchemical Binding Free-Energy Calculations Using Coupled Topologies

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