TR-2013-10 Technical Report-The University of Chicago-Department of Computer Science

RIDGWAY SCOTT; ARIEL FERNANDEZ STIGLIANO

2013-10-01/2013-11-23

Biológica

Tecnol.sanit.y curativa-Medicamentos

Estudio de microestados comprendidos en estructura cristalina de complejos droga-proteina de interes medicinal. An analysis of crystallographically characterized microstates in molecular complexes often reveals metastable dipole-dipole interactions between the binding partners. The sta- tistical mechanical analysis presented in this work demonstrates that these disruptions can paradoxically enhance affinity. The disruption at the microstate level can only be recon- ciled 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.