Hidden electrostatic basis of dynamic allostery in a PDZ domain [Biophysics and Computational Biology]
![Hidden electrostatic basis of dynamic allostery in a PDZ domain [Biophysics and Computational Biology]](/image/eyJ1cmkiOiJodHRwOi8vd3d3LnBuYXMub3JnL2NvbnRlbnQvZWFybHkvMjAxNy8wNi8xOS8xNzA1MzExMTE0L0YxLm1lZGl1bS5naWYiLCJmb3JtYXQiOiJ3ZWJwIiwicXVhbGl0eSI6MTAwLCJub0NhY2hlIjp0cnVlfQ==.webp)
Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to the traditionally used structure-based parameters. There is a significant population shift in the hydrogen-bonded network and salt bridges involving side chains on ligand binding. The ligand creates a local energetic perturbation that propagates in the form of dominolike changes in interresidue interaction pattern. There are significant changes in the nature of specific interactions (nonpolar/polar) between interresidue contacts and accompanied side-chain reorientations that drive the major redistribution of energy. Interestingly, this internal redistribution and rewiring of side-chain interactions led to large cancellations resulting in small change in the overall enthalpy of the protein, thus making it difficult to detect experimentally. In contrast to the prevailing focus on the entropic or dynamic effects, we show that the internal redistribution and population shift in specific electrostatic interactions drive the allosteric modulation in the PDZ3 domain protein.
Publisher URL: http://feedproxy.google.com/~r/Pnas-RssFeedOfEarlyEditionArticles/~3/V2WKIGxe37Y/1705311114.short
DOI: 10.1073/pnas.1705311114
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