Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

47-POS Board 7 Molecular and Metadynamics to Predict Activation in Experimentally Validated Kinase Domain Mutations E. Joseph Jordan 1 , Ravi Radhakrishnan 1,2 . 1 The University of Pennsylvania, Phildelphia, PA, USA, 2 The University of Pennsylvania, Phildelphia, PA, USA. Kinase proteins are important in cell growth and division and are frequently mutated in cancer. Numerous studies have shown a good correlation between increased catalytic efficiency in mutant kinases and increased ability of mutant cell lines to grow in cell culture. Kinases have distinct active and inactive conformations and this makes them amenable to simulations to predict whether mutations bias the conformation to the active state, which should correlate with increased catalytic efficiency. In this study, we run molecular dynamics simulations of a series of experimentally validated mutants from BRAF, HER2, and ALK kinases and compare the dynamics to those of wild type simulations as assessed by both molecular and metadynamics. This allows us to make predictions of the effect of mutations on kinase activation with greater than 60% accuracy using simple metrics like changes in hydrogen bond occupancy during the course of a simulation. We believe that this method could eventually be used in guiding personalized medical treatments as both the number of observed mutations and the number of available drugs increases going forward.

82