Protein structural defects enable pharmaceutical targeting while functionalizing the M2 proton channel

FERNÁNDEZ, ARIEL

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2019 vol. 514 p. 86 - 91

0006-291X

The influenza M2 (22?46) proton channel is therapeutically targetable and a prototype for proton transport across membranes. Conduction initiation, requiring a hydronium formed with exceptionally high pKa, remains nebulous. We tackle the problem by focusing on the dynamic interplay between protein structure and solvent interface. We identify two packing defects in the protein subunits that predict exactly the low and high-affinity drug-binding sites. The latter defect frustrates water coordination, enhancing water basicity and stabilizing the nearby hydronium that forms upon proton penetration in the channel. Thus, the trigger of proton conduction is directly related to the high-affinity binding site. The findings, in quantitative agreement with affinity measurements, are consistent with the targetable functional nature of protein packing defects. These findings enable the design of proton-conducting biomimetic materials, where the epistructure may be engineered to tune the basicity of interfacial water.