PH-selective mutagenesis of protein-protein interfaces: in silico design of therapeutic antibodies with prolonged half-life.

ABSTRACT: Understanding the effects of mutation on pH-dependent protein binding affinity is important in protein design, especially in the area of protein therapeutics. We propose a novel method for fast in silico mutagenesis of protein-protein complexes to calculate the effect of mutation as a function of pH. The free energy differences between the wild type and mutants are evaluated from a molecular mechanics model, combined with calculations of the equilibria of proton binding. The predicted pH-dependent energy profiles demonstrate excellent agreement with experimentally measured pH-dependency of the effect of mutations on the dissociation constants for the complex of turkey ovomucoid third domain (OMTKY3) and proteinase B. The virtual scanning mutagenesis identifies all hotspots responsible for

SUBMITTER: Spassov VZ 

PROVIDER: S-EPMC3601434 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature