Building Tools for Predicting Allosteric Regulation Pathways in Proteins

Allosteric regulation of protein function is a mechanism by which a structural event occurring at one site within a protein’s overall structure causes an effect at another site, and allostery plays a central role in a huge variety of mechanistic pathways in biological systems.  The prediction and modulation of allosteric responses in proteins holds promise for applications in a diverse range of research areas, including drug design and materials engineering.  The structural changes involved in protein allostery include deformations where local elastic moduli play a major role.  Knowledge of the elastic modulus at each atom position or within specific regions in a protein can provide valuable information about the local mobility and stability under conformational deformations.  However, most methods used for calculating local elastic moduli cannot be applied to proteins in a straightforward manner because they require second derivatives of the potentials that describe the interactions amongst a protein's atoms.  To address this issue, we have begun the development of computational methods that enable the measurement of elastic moduli at different positions in a protein in order to build a 3D map of local mechanical properties that can be used to identify pathways of allostery in proteins and protein networks.  Presented here are the results from a preliminary set of protein structural analyses completed using these methods to calculate elastic moduli in an atomistic fashion.