(376ab) Modulating Protein Conformational Dynamics Via Salt-Bridging Interactions

The sequences and three-dimensional structural folds of homologous proteins often fail to explain many striking differences in their functional characteristics, which are attributed to their dynamics in the solution state. The differences in dynamics of closely-related proteins present significant hurdles for structure-based design of small molecules targeting such proteins. In this work, we have studied using atomistic molecular dynamics (MD) simulations the interplay of protein dynamics and their role in affecting binding affinities of ligands in a family of signaling proteins. We hypothesized that protein flexibility can be modulated by incorporating or removing salt-bridging interactions, thereby designing new protein constructs where inhibitor potency can be enhanced or reduced in a predictable way. Presented in this work will be results where we identified several such salt-bridging interactions across various isoforms of signaling proteins and studied mutant proteins that revealed a reduction in potency of inhibition on reducing the protein flexibility.