Energetic and Dynamic Aspects of the Affinity Maturation Process: Characterizing Improved Variants from the Bevacizumab Antibody with Molecular Simulations

Antibody affinity maturation is one of the fundamental processes of
immune defense against invading pathogens. From the biological point of
view, the clonal selection hypothesis represents the most accepted
mechanism to explain how mutations increasing the affinity for target
antigens are introduced and selected in antibody molecules. However,
understanding at the molecular level how protein modifications, such as
point mutation, can modify and modulate the affinity of an antibody for
its antigen is still a major open issue in molecular biology. In this
paper, we address various aspects of this problem by analyzing and
comparing atomistic simulations of 17 variants of the bevacizumab
antibody, all directed against the common target protein VEGF-A. In
particular, we examine MD-based descriptors of the internal energetics
and dynamics of mutated antibodies and their possible correlations with
experimentally determined affinities for the antigens. Our results show
that affinity improvement is correlated with a variation of the internal
stabilization energy of the antibody molecule when bound to the antigen,
compensated by the variation in the interaction energy between the
antigen and the antibody, paralleled by an overall modulation of
internal coordination within the antibody molecular structure. A
possible model of the mechanism of rigidification and of the main
residues involved is proposed. Overall, our results can help in
understanding the molecular determinants of antigen recognition and have
implications in the rational design of new antibodies with optimized
affinities.