期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 56, 期 14, 页码 3833-3837出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201609409
关键词
enthalpy-entropy compensation; hydrophobic effects; mutational analysis; protein-ligand interactions
资金
- National Science Foundation [1152196]
- U.S. National Institutes of Health (the National Institute of General Medical Sciences)
- Howard Hughes Medical Institute
- U.S. Department of Energy (Director, Office of Science, Office of Basic Energy Sciences) [DE-AC02-05CH11231]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1152196] Funding Source: National Science Foundation
This study uses mutants of human carbonic anhydrase (HCAII) to examine how changes in the organization of water within a binding pocket can alter the thermodynamics of protein-ligand association. Results from calorimetric, crystallographic, and theoretical analyses suggest that most mutations strengthen networks of water-mediated hydrogen bonds and reduce binding affinity by increasing the enthalpic cost and, to a lesser extent, the entropic benefit of rearranging those networks during binding. The organization of water within a binding pocket can thus determine whether the hydrophobic interactions in which it engages are enthalpy-driven or entropy-driven. Our findings highlight a possible asymmetry in protein-ligand association by suggesting that, within the confines of the binding pocket of HCAII, binding events associated with enthalpically favorable rearrangements of water are stronger than those associated with entropically favorable ones.
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