The electrostatics is one of the major forces and energies contributing to protein-protein binding and is expected to be affected by mutations (site directed in vitro and naturally occurring mutations). This investigation utilizes a development of a protocol, molecular mechanics Poisson-Boltzmann surface accessibility (MMPB/SA) method to compute the change of the binding free (??G) energy upon single point mutation and to optimize the parameters against experimentally measured ??G. The results are analyzed with respect to the electrostatic contribution to the calculated ??G. It is demonstrated that a replacement of naturally occurring charged amino acids at the protein interface almost always decreases the binding affinity. This observation is rationalized with the specificity of pair-wise interactions, which are optimized in the native protein-protein complexes. Any disruption of the electrostatic network across the interface is expected to be reducing the binding affinity.

Electrostatics plays significant role in changes of the protein-protein affinity due to missense mutations

246th National Meeting (2013)

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