Non-Debye frustrated hydration steers biomolecular association: interfacial tension for the drug designer.
Many cellular functions involve the assembly of biomolecular complexes, a process mediated by water that gets displaced as subunits bind. This process affects water frustration, that is, the number of unmet hydrogen-bonding opportunities at the protein-water interface. By searching for least-frustrated aqueous interfaces, this study delineates the role of frustration in steering molecular assemblage. The search entails a trajectory sampling using a functional that measures the gradient of frustration and computing the resulting non-Debye electrostatics within relaxation times for coupled protein-water systems. The minimal frustration principle is validated against spectroscopic measurements of frustration-dependent dielectric relaxation, affinity scanning of protein-protein interfaces, and NMR-inferred association propensities of protein-complex intermediates. The methods are applied to drug design, revealing the targetable nature of the aqueous interface.
Argentine Mathematics Institute (I. A. M.), National Research Council (CONICET), Buenos Aires, Argentina. ariel@afinnovation.com.|AF Innovation, Pharmaceutical Consultancy GmbH, Buenos Aires, Argentina. ariel@afinnovation.com.
Ariel
A
Fernández
D015195:Drug Design; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011506:Proteins / Q000737:chemistry*; D013499:Surface Properties; D013500:Surface Tension; D014867:Water / Q000737:chemistry*
D011506:Proteins; D014867:Water
aqueous interface; drug design; molecular modeling; protein associations; structural biology