Determination of the differential effects of hydrogen bonding and water release on the binding of FK506 to native and Tyr82-->Phe82 FKBP-12 proteins using free energy simulations

Journal of Molecular Biology
D A Pearlman, P R Connelly

Abstract

We use the thermodynamic integration technique to calculate the free energy associated with the Tyr82-->Phe82 mutation (Y82F) in the protein FKBP-12, both free and bound to known inhibitor FK506 (tacrolimis). We find that the net difference in free energy for the two changes is 0.85 kcal/mol, with the binding of FK506 relatively more favorable for the native protein than the mutant. This net energy compares very favorably with the experimentally measured value of 0.60 kcal/mol. The results indicate that the relatively better binding of FK506 to the native protein is driven by the favorable entropy associated with the release of water molecules from the protein when the ligand binds. For a variety of reasons, modest size of the system, smallness of the change being examined, rapid convergence of the ensemble that needs to be determined and use of statistical estimates to control sampling, we have been able to carry out atypically reliable and reproducible free energy calculations for this protein system. Free energy changes for the two simulations (Y82F FKBP-12/FK506 and Y82F FKBP-12) have been calculated a total of eight times each, to compare a variety of different methodological choices and to ensure that the results are stat...Continue Reading

Citations

Sep 17, 2015·Interdisciplinary Sciences, Computational Life Sciences·Ganesh Prasad Mishra, Rajesh Sharma
May 21, 1999·Proteins·B K ShoichetI D Kuntz
Dec 24, 1997·The Journal of Peptide Research : Official Journal of the American Peptide Society·A Melo, M J Ramos
Nov 6, 2012·The Journal of Biological Chemistry·Latifa ElantakClaudine Schiff
Apr 28, 2021·Journal of Computer-aided Molecular Design·Huizhen GeXiaojun Yao
Oct 10, 1998·Journal of Medicinal Chemistry·M L Lamb, W L Jorgensen
Sep 12, 2006·Biochemical and Biophysical Research Communications·Christopher A LipinskiJoseph C Loftus
Jan 14, 2012·Journal of Medicinal Chemistry·David J HugginsBruce Tidor
Sep 17, 2020·Journal of Chemical Information and Modeling·Tai-Sung LeeDarrin M York
Oct 16, 2010·Structure·Michael KochGünter Fritz

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