Packing defects functionalize soluble proteins

FEBS Letters
Ariel Fernández

Abstract

This work explores the participation of protein packing defects, the so-called dehydrons, in biochemical events. We delineate the enabling role of dehydrons as activators of nucleophilic groups. This activation results from the induction of chemical basicity in interfacial water molecules, promoting deprotonation of adjacent nucleophiles. Through multiple steering molecular dynamics with pulling along the proton-displacement coordinate, we show that nucleophilic groups are functionally enabled by nearby dehydrons that promote proton transference. The computations are validated against experimentally determined pKa decreases at functional sites and biochemical probes of deregulated catalytic activity arising from dehydron-generating mutations.

References

Nov 1, 1996·Protein Science : a Publication of the Protein Society·L A PlesniakL P McIntosh
Nov 18, 2000·The Journal of Biological Chemistry·E R Goedken, S Marqusee
Dec 9, 2004·Journal of Computational Chemistry·S ChiodoE Sicilia
Oct 25, 2008·Chemical Society Reviews·Ariel Fernández, Alejandro Crespo
Jan 29, 2009·Angewandte Chemie·Hans Martin Senn, Walter Thiel
Apr 6, 2013·Biochemistry·Marc W van der Kamp, Adrian J Mulholland
Jun 21, 2013·The Journal of Chemical Physics·Ariel Fernández Stigliano
Jun 28, 2013·The Journal of Biological Chemistry·Shruti AgarwalLars Rönnstrand
Apr 29, 2014·Journal of Physics. Condensed Matter : an Institute of Physics Journal·Ariel Fernández

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Citations

Jan 15, 2016·FEBS Letters·Ariel Fernández
Oct 21, 2015·Drug Discovery Today·Ariel Fernández, L Ridgway Scott

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