Chemical Functionality of the Aqueous Interface in Soluble Proteins
Building upon a non-Debye multiscale treatment of water dielectrics, this chapter reveals the chemical functionality of biomolecular interfaces. More specifically, it asserts the chemical basicity of interfacial water enveloping nanoscale structural defects (dehydrons) in soluble proteins and establishes the participation of dehydrons in biochemical events. The quasi-reactant status of dehydrons is already implied by their significant concentration in the vicinity of an enzymatically active site, delineating their role as promoters or enhancers of catalytic activity. We further delineate the enabling role of dehydrons as activators of nucleophilic groups engaged in catalysis. 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. The computations are validated against experimentally evidence on specific pKa decreases at functional sites and on degenerative deregulation of catalytic activity arising from dehydron-generating mutations. The proton-acceptor role of dehydrons, or rather, of interfacial water enveloping dehydrons, is likely to revolutionize our understanding of biochemical mechanism. It is probable that most if not all transesterification reactions in biochemistry requiring the activation of a nucleophilic group will need to be rewritten to incorporate the catalytic enablement provided by nearby dehydrons. A new biochemical quasi-reactant has been thus discovered demanding a vast revision of the mechanistic literature in bio-organic chemistry.
KeywordsInterfacial Water Proton Acceptor Chemical Functionality Nucleophilic Group Aqueous Interface
- 9.The Uniprot Consortium (2014) Activities at the universal protein resource (UniProt) Nuc Acids Res 42:D191–D198Google Scholar
- 10.Hardie DG (ed) (1999) Protein phosphorylation: a practical approach. Oxford University Press, Oxford, New YorkGoogle Scholar
- 16.Fernández A (2014) Protein structural defects are enablers and stimulators of enzyme catalysis, Scientist Ariel Fernandez Finds. Market Watch (The Wall Street Journal). http://www.marketwatch.com/story/protein-structural-defects-are-enablers-and-stimulators-of-enzyme-catalysis-scientist-ariel-fernandez-finds-2014-07-14. Published 14 July, 2014
- 18.Li H, Robertson AD, Jensen JH (2005) Very fast empirical prediction and rationalization of protein pKa values. Proteins: Struct Funct Bioinf 61:704–721Google Scholar
- 34.Fernandez A (2015) Packing defects functionalize soluble proteins. FEBS Lett 589:967–973Google Scholar