A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations

  1. Yong Duan1,*,
  2. Chun Wu1,
  3. Shibasish Chowdhury1,
  4. Mathew C. Lee1,
  5. Guoming Xiong1,
  6. Wei Zhang1,
  7. Rong Yang1,
  8. Piotr Cieplak2,3,
  9. Ray Luo2,
  10. Taisung Lee2,3,
  11. James Caldwell2,
  12. Junmei Wang2,
  13. Peter Kollman2,†

Article first published online: 25 SEP 2003

DOI: 10.1002/jcc.10349

Issue

Journal of Computational Chemistry

Journal of Computational Chemistry

Volume 24, Issue 16, pages 1999–2012, December 2003

Additional Information

How to Cite

Duan, Y., Wu, C., Chowdhury, S., Lee, M. C., Xiong, G., Zhang, W., Yang, R., Cieplak, P., Luo, R., Lee, T., Caldwell, J., Wang, J. and Kollman, P. (2003), A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J. Comput. Chem., 24: 1999–2012. doi: 10.1002/jcc.10349

Author Information

  1. 1

    Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716

  2. 2

    Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94143

  3. 3

    Accelrys Inc., 9685 Scranton Rd, San Diego, California 92121

  1. †

    Deceased.

*Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716

Publication History

  1. Issue published online: 25 SEP 2003
  2. Article first published online: 25 SEP 2003
  3. Manuscript Accepted: 1 JUL 2003
  4. Manuscript Received: 7 APR 2003

Funded by

  • NIH Research Source. Grant Number: CRR-15588
  • National Institute of General Medical Sciences. Grant Numbers: GM-64458, GM-67168, GM-29072
  • The State of Delaware and University of Delaware Research Fund

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Keywords:

  • point-charge force field;
  • quantum mechanical calculations;
  • molecular mechanics simulations

Abstract

Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report the development of a third-generation point-charge all-atom force field for proteins. Following the earlier approach of Cornell et al., the charge set was obtained by fitting to the electrostatic potentials of dipeptides calculated using B3LYP/cc-pVTZ//HF/6-31G** quantum mechanical methods. The main-chain torsion parameters were obtained by fitting to the energy profiles of Ace-Ala-Nme and Ace-Gly-Nme di-peptides calculated using MP2/cc-pVTZ//HF/6-31G** quantum mechanical methods. All other parameters were taken from the existing AMBER data base. The major departure from previous force fields is that all quantum mechanical calculations were done in the condensed phase with continuum solvent models and an effective dielectric constant of ε = 4. We anticipate that this force field parameter set will address certain critical short comings of previous force fields in condensed-phase simulations of proteins. Initial tests on peptides demonstrated a high-degree of similarity between the calculated and the statistically measured Ramanchandran maps for both Ace-Gly-Nme and Ace-Ala-Nme di-peptides. Some highlights of our results include (1) well-preserved balance between the extended and helical region distributions, and (2) favorable type-II poly-proline helical region in agreement with recent experiments. Backward compatibility between the new and Cornell et al. charge sets, as judged by overall agreement between dipole moments, allows a smooth transition to the new force field in the area of ligand-binding calculations. Test simulations on a large set of proteins are also discussed. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1999–2012, 2003

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