title: Packing defects functionalize soluble proteins.
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.
authors.affiliation: Argentine Institute of Mathematics (I. A. M.), National Research Council (CONICET), Buenos Aires 1083, Argentina. Electronic address: ariel@afinnovation.com.
authors.forename: Ariel
authors.initials: A
authors.lastname: Fernández
mesh_terms: D001665:Binding Sites; D004735:Energy Transfer; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D011506:Proteins; D014867:Water
keywords: Catalytic stimulation; Enzyme catalysis; Molecular biophysics; Packing defect; Soluble protein; Structural biology