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Biophysical Journal 87:1618-1630 (2004)
© 2004 The Biophysical Society

How Optimal Are the Binding Energetics of Barnase and Barstar?

Ting Wang *, Sanja Tomic {dagger}, Razif R. Gabdoulline * and Rebecca C. Wade *

* Molecular and Cellular Modeling Group, EML Research, 69118 Heidelberg, Germany; and {dagger} Ruder Boskovic Institute, HR-10001 Zagreb, Croatia

Correspondence: Address reprint requests to Rebecca C. Wade, Tel.: 49-6221-533-247; Fax: 49-6221-533-298; Email: rebecca.wade{at}eml-r.villa-bosch.de.

The extracellular ribonuclease barnase and its intracellular inhibitor barstar bind fast and with high affinity. Although extensive experimental and theoretical studies have been carried out on this system, it is unclear what the relative importance of different contributions to the high affinity is and whether binding can be improved through point mutations. In this work, we first applied Poisson-Boltzmann electrostatic calculations to 65 barnase-barstar complexes with mutations in both barnase and barstar. The continuum electrostatic calculations with a van der Waals surface dielectric boundary definition result in the electrostatic interaction free energy providing the dominant contribution favoring barnase-barstar binding. The results show that the computed electrostatic binding free energy can be improved through mutations at W44/barstar and E73/barnase. Furthermore, the determinants of binding affinity were quantified by applying COMparative BINding Energy (COMBINE) analysis to derive quantitative structure-activity relationships (QSARs) for the 65 complexes. The COMBINE QSAR model highlights ~20 interfacial residue pairs as responsible for most of the differences in binding affinity between the mutant complexes, mainly due to electrostatic interactions. Based on the COMBINE model, together with Brownian dynamics simulations to compute diffusional association rate constants, several mutants were designed to have higher binding affinities than the wild-type proteins.




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