Comparison of experimental and computational functional group mapping of an RNase A structure: Implications for computer-aided drug design

Diane Joseph-McCarthy, Alexander A. Fedorov, Steven C. Almo

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

One relatively new computational approach to the drug discovery process involves calculating functional group maps of a target structure. Experimental functional group mapping techniques have also recently emerged. In this paper, the structure of RNase A with two bound formates (i.e. carboxylate functionalities) is used as a model system to test the computational methodology. Functional group maps of the RNase A structure were calculated using the Multiple Copy Simultaneous Search (MCSS) method and compared with experimentally determined formate and water positions. The calculations indicate that the protonation state of active-site histidines determines the ability of the enzyme to bind formate. The results also suggest an ordered binding mechanism for the two formates. An improved strategy for using the MCSS method to design new candidate ligands is discussed.

Original languageEnglish (US)
Pages (from-to)773-780
Number of pages8
JournalProtein Engineering
Volume9
Issue number9
StatePublished - Sep 1 1996

Keywords

  • Computational drug design
  • Functional group mapping
  • Multiple Copy Simultaneous Search (MCSS)
  • RNase A

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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