Allosteric long-range interactions which characterize the conformational and energetic dynamics of many protein systems such as PDZ-domain containing systems proves an important focus in many forms of molecular dynamics (MD) research for understanding the dynamics underlying protein interaction and potential drug delivery pathways. A sector-based analysis identifies a network of residues referred to as a “sector” significantly involved in protein allostery. PDZ allosterism has been investigated through both a coevolutionary lens and with more recent MD-sector based approach, a residue-pairwise motionally-covariant lens. Although the importance of conformational change has been demonstrated to be important in understanding PDZ-domain dynamics, evidence of dynamic allosteric activity in PDZ-based systems, allosterism in the absence of macromolecular conformational change, also point towards the importance of energetic approaches. In the present project, we use a novel energetic analysis to investigate the role of energetic pathways within CRIB-par6 allostery by analyzing electrostatic interactions temporally embedded over the course of a MD-simulation. In conjunction with a motional dynamics approach endowed by MD-sector analysis towards PDZ allosterism, the present analysis aims to investigate the energetic dynamics between protein residues at atomic resolution for the PDZ containing CRIB-Par6 system.

MD-based energetic heat kernel analysis: Insights to PDZ allosterism

ACS Spring 2022

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