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J Med Chem. 2013 Apr 11;56(7):2874-84. doi: 10.1021/jm301823g. Epub 2013 Mar 20.

The impact of introducing a histidine into an apolar cavity site on docking and ligand recognition.

Author information

1
Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth Street, San Francisco, California 94158-2550, United States.

Abstract

Simplified model binding sites allow one to isolate entangled terms in molecular energy functions. Here, we investigate the effects on ligand recognition of the introduction of a histidine into a hydrophobic cavity in lysozyme. We docked 656040 molecules and tested 26 highly and nine poorly ranked. Twenty-one highly ranked molecules bound and five were false positives, while three poorly ranked molecules were false negatives. In the 16 X-ray complexes now known, the docking predictions overlaid well with the crystallographic results. Although ligand enrichment was high, the false negatives, the false positives, and the inability to rank order illuminated weaknesses in our scoring, particularly overweighed apolar and underweighted polar terms. Adjusting these led to new problems, reflecting the entangled nature of docking scoring functions. Changes in ligand affinity relative to other lysozyme cavities speak to the subtleties of molecular recognition even in these simple sites and to their relevance for testing different models of recognition.

PMID:
23473072
PMCID:
PMC3624796
DOI:
10.1021/jm301823g
[Indexed for MEDLINE]
Free PMC Article

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