Atomistic mechanisms of human TRPA1 activation by electrophile irritants through molecular dynamics simulation and mutual information analysis

Journal article

Protein dynamics are central to their function. Enzymes must sample a range of conformations that preferentially bind substrate, order reactive groups for catalysis, and release products. The same fundamental principle applies to proteins which regulate their substrate affinity to maintain cellular conditions and communicate signals. Understanding how a protein’s sequence and structure influence dynamics remains a fundamental challenge in biophysics with major implications for de novo protein design and therapeutic development. This dissertation details a novel computational method that reveals an underlying feature of proteins connecting sequence, structure, and dynamics. After sampling a protein’s conformations at many reduced Hamiltonians (effective temperatures), all of the inter-residue contact probabilities are obtained as a function of energy. Principal component analysis is applied to reveal energy-dependent contact patterns. Correlated and highly energy-sensitive interactions are revealed by large magnitude loading scores on the principal components. This Chemically Accurate Contact Response Analysis (ChACRA) and its application to investigations of enzymatic activity tuning, heat sensing, and allostery in several protein systems is discussed

Authors: Habgood, M; Seiferth, D; Zaki, A-M; Alibay, I; Biggin, PC

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Scientific Reports
• Volume: 12
• Issue: 1
• Pages: 4929-4929
• Article number: 4929
• Publication date: 2022-03-23
• DOI: 10.1038/s41598-022-08824-7
• EISSN: 2045-2322
• ISSN: 2045-2322
• Language: English
• Keywords: Enzyme; Electrophile; Biophysics; Molecular dynamics; Biochemistry; Biology; Computational chemistry; Chemistry; Allosteric regulation