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Journal of Chemical Physics / Volume 135 / Issue 23 / COMMUNICATIONS
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J. Chem. Phys. 135, 231101 (2011); http://dx.doi.org/10.1063/1.3671638 (4 pages)

Communication: Quantum polarized fluctuating charge model: A practical method to include ligand polarizability in biomolecular simulations

S. Roy Kimura, Ramkumar Rajamani, and David R. Langley

Department of Computer-Assisted Drug Design, Bristol-Myers Squibb R & D, 5 Research Parkway, Wallingford, Connecticut 06492, USA

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(Received 20 October 2011; accepted 2 December 2011; published online 21 December 2011)

We present a simple and practical method to include ligand electronic polarization in molecular dynamics (MD) simulation of biomolecular systems. The method involves periodically spawning quantum mechanical (QM) electrostatic potential (ESP) calculations on an extra set of computer processors using molecular coordinate snapshots from a running parallel MD simulation. The QM ESPs are evaluated for the small-molecule ligand in the presence of the electric field induced by the protein, solvent, and ion charges within the MD snapshot. Partial charges on ligand atom centers are fit through the multi-conformer restrained electrostatic potential (RESP) fit method on several successive ESPs. The RESP method was selected since it produces charges consistent with the AMBER/GAFF force-field used in the simulations. The updated charges are introduced back into the running simulation when the next snapshot is saved. The result is a simulation whose ligand partial charges continuously respond in real-time to the short-term mean electrostatic field of the evolving environment without incurring additional wall-clock time. We show that (1) by incorporating the cost of polarization back into the potential energy of the MD simulation, the algorithm conserves energy when run in the microcanonical ensemble and (2) the mean solvation free energies for 15 neutral amino acid side chains calculated with the quantum polarized fluctuating charge method and thermodynamic integration agree better with experiment relative to the Amber fixed charge force-field.

© 2011 American Institute of Physics

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KEYWORDS and PACS

Keywords

bioelectric phenomena, biothermics, free energy, molecular biophysics, molecular configurations, molecular dynamics method, proteins, solvation

PACS

  • 87.15.Pc

    Electronic and electrical properties

  • 36.20.Ey

    Conformation (statistics and dynamics)

  • 36.20.Kd

    Electronic structure and spectra

  • 87.19.Pp

    Biothermics and thermal processes in biology

  • 87.15.ak

    Monte Carlo simulations

  • 87.15.B-

    Structure of biomolecules

ARTICLE DATA

Digital Object Identifier
http://dx.doi.org/10.1063/1.3671638

PUBLICATION DATA

ISSN

0021-9606 (print)  
1089-7690 (online)

Publisher

$abstract.society.value is a Member of CrossRef American Institute of Physics

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Figures (3) Tables (2)

Figures (click on thumbnails to view enlargements)

FIG.1
Summary of the quantum polarized fluctuating charge (QPFC) methodology. In the current implementation, the QM charge fitting is done on the ligand at each interval, τ.

FIG.1 Download High Resolution Image (.zip file) | Export Figure to PowerPoint

FIG.2
Calculated and experimental solvation free energies (kcal/mol). qpfc_full refers to the results when the un-scaled full RESP charges were used in the FEP calculations. qpfc_0.9 refers to the case when those charges were scaled by a factor of 0.9 during the QPFC simulations, and the resulting mean charges were used in the FEP calculations. Experimental values taken from Ref. 27.

FIG.2 Download High Resolution Image (.zip file) | Export Figure to PowerPoint

FIG.3
Total energy trajectory showing heating and equilibration phases in NVT ensembles, and QPFC simulation in NVE ensemble starting from 600 ps into the simulation (blue line). The discontinuities in the energy (blue line) during the QPFC NVE phase correspond to the replacement of ligand charges with newly calculated ones. The red line shows the result of adding back the change in electrostatic energy (ΔECoulombic) to the total QPFC NVE energy each time the charges are updated. Note that the total energy is now conserved (red line).

FIG.3 Download High Resolution Image (.zip file) | Export Figure to PowerPoint

Tables

Table I. Amino acid solvation-free energy calculations versus experiment.

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Table II. Simulation details.

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