Application of the multimolecule and multiconformational RESP methodology to biopolymers: Charge derivation for DNA, RNA, and proteins

Authors

  • Piotr Cieplak,

    1. Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143
    Current affiliation:
    1. Dept. Chem., U. of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
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  • Wendy D. Cornell,

    1. Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143
    Current affiliation:
    1. EMBO Labs, Heidelberg, Germany
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  • Christopher Bayly,

    1. Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143
    Current affiliation:
    1. Merck Frost Inc., C. P. 1005 Point Claire, Dorval Quebec, H9R 4P8 Canada
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  • Peter A. Kollman

    Corresponding author
    1. Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143
    • Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143
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Abstract

We present the derivation of charges of ribo- and deoxynucleosides, nucleotides, and peptide fragments using electrostatic potentials obtained from ab initio calculations with the 6-31G* basis set. For the nucleic acid fragments, we used electrostatic potentials of the four deoxyribonucleosides (A, G, C, T) and four ribonucleosides (A, G, C, U) and dimethylphosphate. The charges for the deoxyribose nucleosides and nucleotides are derived using multiple-molecule fitting and restrained electrostatic potential (RESP) fits,1,2 with Lagrangian multipliers ensuring a net charge of 0 or ± 1. We suggest that the preferred approach for deriving charges for nucleosides and nucleotides involves allowing only C1′ and H1′ of the sugar to vary as the nucleic acid base, with the remainder of sugar and backbone atoms forced to be equivalent. For peptide fragments, we have combined multiple conformation fitting, previously employed by Williams3 and Reynolds et al.,4 with the RESP approach1,2 to derive charges for blocked dipeptides appropriate for each of the 20 naturally occuring amino acids. Based on our results for propyl amine,1,2 we suggest that two conformations for each peptide suffice to give charges that represent well the conformationally dependent electrostatic properties of molecules, provided that these two conformations contain different values of the dihedral angles that terminate in heteroatoms or hydrogens attached to heteroatoms. In these blocked dipeptide models, it is useful to require equivalent N—H and C[DOUBLE BOND]O charges for all amino acids with a given net charge (except proline), and this is accomplished in a straightforward fashion with multiple-molecule fitting. Finally, the application of multiple Lagrangian constraints allows for the derivation of monomeric residues with the appropriate net charge from a chemically blocked version of the residue. The multiple Lagrange constraints also enable charges from two or more molecules to be spliced together in a well-defined fashion. Thus, the combined use of multiple molecules, multiple conformations, multiple Lagrangian constraints, and RESP fitting is shown to be a powerful approach to deriving electrostatic charges for biopolymers. © 1995 John Wiley & Sons, Inc.

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