A disruptive dipole-dipole alignment promotes a stable molecular association

L. Ridgway Scott; Ariel Fernandez Stigliano. 22 November, 2013.
Communicated by L. Ridgway Scott.


An analysis of crystallographically characterized microstates in molecular complexes often reveals metastable dipole-dipole interactions between the binding partners. The statistical mechanical analysis presented in this work demonstrates that these disruptions can paradoxically enhance affinity. The disruption at the microstate level can only be reconciled with the decrease in free energy of association once the full conformational ensemble is considered, yielding both a net decrease in enthalpy and increase in entropy. The full ensemble cannot easily be inferred from crystallographic information. These microstate mismatches are shown to be common in drug-target interactions for recently developed cancer drugs. The reverse engineering of such compounds presented here has suggested that these mismatches at the microstate level may inspire molecular designs that enhance target affinity.

Original Document

The original document is available in PDF (uploaded 22 November, 2013 by L. Ridgway Scott).