Protein internal motions or dynamics are intimately coupled to molecular function and its regulation. However, detailed mechanisms on how a protein molecule harnesses thermal fluctuations for function remain elusive. An effective way to understand a complex system is to introduce small variations or perturbations to examine how the system responds. Practically, this approach has been implemented in laboratories to understand protein function via site-directed mutagenesis. On the other hand, nature has done similar “experiments” in which natural proteins evolved to acquire diversity through mutations and the subsequent natural selection or genetic drift. During evolution, certain patterns of dynamics must be conserved to retain the core protein function, whereas variable dynamics in synergy with variable sequences underlie the functional specificity. Hence, a careful examination of dynamics across extant homologous proteins provide unprecedented opportunity to uncover the complex structure-dynamics-function relationship. Here we describe a comparative study of the conformational dynamics across the cyclophilin family, a group of enzymes catalyzing the peptidyl-prolyl cis-trans isomerization and model systems where dynamics determine function. With a combined approach of molecular dynamics simulations and residue-residue contact analysis, we uncovered the allosteric mechanisms underlying the molecular recognition and catalysis in cyclophilins. Collectively, our results provide a framework where both common and specific functional mechanisms can be understood with an evolutionary analysis of contact dynamics.

Evolutionarily conserved and divergent residue-residue contact dynamics provide insights into the allosteric regulation of cyclophilins

255th National Meeting (2018)

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