CVN, a strong HIV inhibitor, binds to oligomannose displaying the Mana1-2Mana motif. (Bewley, C. A. Structure, 2001  , 9, 931-940) Glu41 of CVN is a residue that is known to form strong hydrogen bonds with the sugar moiety. In order to better understand the role of Glu41 in binding to these sugars we have carried out a set of computational free energy studies. (Ramadugu, S., Li, Z. et al. Biochemistry, 2014  , DOI: 10.1021/bi4014159) Specifically, we have utilized the thermodynamic integration and Bennett Acceptance Ratio approaches to estimate the free energy changes that result from the mutation of residue Glu41 of P51G-m4-CVN (Fromme, R. et al. Biochemistry, 2007  , 46, 9199-9207) into Ala and Gly. The analysis of our results is split into electrostatic and dispersion contributions to the free energy. Interestingly, we find that whereas the Coulombic contribution to the free energy significantly favors Glu41, there are significant cancellations because of dispersion interactions. In more general terms, we learn that it is not enough that structural hydrogen bond interactions are observed between an amino acid and the ligand to infer that said ligand is necessarily key to the overall free energetics of binding.

Difference in dimannose binding affinities between P51G-m4-CVN and its mutants at position 41

248th National Meeting (2014)

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