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Title: Development of CHARMM-Compatible Force-Field Parameters for Cobalamin and Related Cofactors from Quantum Mechanical Calculations

Abstract

Corrinoid cofactors such as cobalamin are used by many enzymes and are essential for most living organisms. Therefore, there is broad interest in investigating cobalamin–protein interactions with molecular dynamics simulations. Previously developed parameters for cobalamins are based mainly on crystal structure data. Here, we report CHARMM-compatible force field parameters for several corrinoids developed from quantum mechanical calculations. We provide parameters for corrinoids in three oxidation states, Co 3+, Co 2+, and Co 1+, and with various axial ligands. Lennard-Jones parameters for the cobalt center in the Co(II) and Co(I) states were optimized using a helium atom probe, and partial atomic charges were obtained with a combination of natural population analysis (NPA) and restrained electrostatic potential (RESP) fitting approaches. The Force Field Toolkit was used to optimize all bonded terms. The resulting parameters, determined solely from calculations of cobalamin alone or in water, were then validated by assessing their agreement with density functional theory geometries and by analyzing molecular dynamics simulation trajectories of several corrinoid proteins for which X-ray crystal structures are available. In each case, we obtained excellent agreement with the reference data. In comparison to previous CHARMM-compatible parameters for cobalamin, we observe a better agreement for the fold anglemore » and lower RMSD in the cobalamin binding site. In conclusion, the approach described here is readily adaptable for developing CHARMM-compatible force-field parameters for other corrinoids or large biomolecules.« less

Authors:
 [1]; ORCiD logo [2]; ORCiD logo [1]
  1. Georgia Inst. of Technology, Atlanta, GA (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1459308
Alternate Identifier(s):
OSTI ID: 1480247
Grant/Contract Number:  
AC05-00OR22725; AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Chemical Theory and Computation
Additional Journal Information:
Journal Volume: 14; Journal Issue: 2; Journal ID: ISSN 1549-9618
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Pavlova, Anna, Parks, Jerry M., and Gumbart, James C. Development of CHARMM-Compatible Force-Field Parameters for Cobalamin and Related Cofactors from Quantum Mechanical Calculations. United States: N. p., 2018. Web. doi:10.1021/acs.jctc.7b01236.
Pavlova, Anna, Parks, Jerry M., & Gumbart, James C. Development of CHARMM-Compatible Force-Field Parameters for Cobalamin and Related Cofactors from Quantum Mechanical Calculations. United States. doi:10.1021/acs.jctc.7b01236.
Pavlova, Anna, Parks, Jerry M., and Gumbart, James C. Mon . "Development of CHARMM-Compatible Force-Field Parameters for Cobalamin and Related Cofactors from Quantum Mechanical Calculations". United States. doi:10.1021/acs.jctc.7b01236. https://www.osti.gov/servlets/purl/1459308.
@article{osti_1459308,
title = {Development of CHARMM-Compatible Force-Field Parameters for Cobalamin and Related Cofactors from Quantum Mechanical Calculations},
author = {Pavlova, Anna and Parks, Jerry M. and Gumbart, James C.},
abstractNote = {Corrinoid cofactors such as cobalamin are used by many enzymes and are essential for most living organisms. Therefore, there is broad interest in investigating cobalamin–protein interactions with molecular dynamics simulations. Previously developed parameters for cobalamins are based mainly on crystal structure data. Here, we report CHARMM-compatible force field parameters for several corrinoids developed from quantum mechanical calculations. We provide parameters for corrinoids in three oxidation states, Co3+, Co2+, and Co1+, and with various axial ligands. Lennard-Jones parameters for the cobalt center in the Co(II) and Co(I) states were optimized using a helium atom probe, and partial atomic charges were obtained with a combination of natural population analysis (NPA) and restrained electrostatic potential (RESP) fitting approaches. The Force Field Toolkit was used to optimize all bonded terms. The resulting parameters, determined solely from calculations of cobalamin alone or in water, were then validated by assessing their agreement with density functional theory geometries and by analyzing molecular dynamics simulation trajectories of several corrinoid proteins for which X-ray crystal structures are available. In each case, we obtained excellent agreement with the reference data. In comparison to previous CHARMM-compatible parameters for cobalamin, we observe a better agreement for the fold angle and lower RMSD in the cobalamin binding site. In conclusion, the approach described here is readily adaptable for developing CHARMM-compatible force-field parameters for other corrinoids or large biomolecules.},
doi = {10.1021/acs.jctc.7b01236},
journal = {Journal of Chemical Theory and Computation},
issn = {1549-9618},
number = 2,
volume = 14,
place = {United States},
year = {2018},
month = {1}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Figures / Tables:

Scheme 1: Scheme 1:: (A) Chemical structure of cobalamin. (B) Standard PDB atom numbering for cobalamin.

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