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Open AccessArticle

Allostery and Epistasis: Emergent Properties of Anisotropic Networks

Department of Physics and Center for Biological Physics, Arizona State University, Tempe, AZ 85287, USA
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Entropy 2020, 22(6), 667; https://doi.org/10.3390/e22060667
Received: 24 April 2020 / Revised: 2 June 2020 / Accepted: 8 June 2020 / Published: 16 June 2020
Understanding the underlying mechanisms behind protein allostery and non-additivity of substitution outcomes (i.e., epistasis) is critical when attempting to predict the functional impact of mutations, particularly at non-conserved sites. In an effort to model these two biological properties, we extend the framework of our metric to calculate dynamic coupling between residues, the Dynamic Coupling Index (DCI) to two new metrics: (i) EpiScore, which quantifies the difference between the residue fluctuation response of a functional site when two other positions are perturbed with random Brownian kicks simultaneously versus individually to capture the degree of cooperativity of these two other positions in modulating the dynamics of the functional site and (ii) DCIasym, which measures the degree of asymmetry between the residue fluctuation response of two sites when one or the other is perturbed with a random force. Applied to four independent systems, we successfully show that EpiScore and DCIasym can capture important biophysical properties in dual mutant substitution outcomes. We propose that allosteric regulation and the mechanisms underlying non-additive amino acid substitution outcomes (i.e., epistasis) can be understood as emergent properties of an anisotropic network of interactions where the inclusion of the full network of interactions is critical for accurate modeling. Consequently, mutations which drive towards a new function may require a fine balance between functional site asymmetry and strength of dynamic coupling with the functional sites. These two tools will provide mechanistic insight into both understanding and predicting the outcome of dual mutations. View Full-Text
Keywords: epistasis; allostery; elastic network model; protein conformational dynamics epistasis; allostery; elastic network model; protein conformational dynamics
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Campitelli, P.; Ozkan, S.B. Allostery and Epistasis: Emergent Properties of Anisotropic Networks. Entropy 2020, 22, 667.

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