Kinases are important drug targets for cancer and a host of other diseases.  Adjacent to the active site of the kinase catalytic domain is a three-residue sequence DFG, which is at the start of the activation loop. In the kinase active state, the sidechain of the DFG-aspartate points into the active site, while that of the DFG-phenylalanine points the opposite direction. However, in the kinase inactive state, the sidechains of the DFG aspartate and phenylalanine swap positions; this is known as the DFG-flip. In the past decade, many research groups have attempted to understand the DFG-flip; however, the detailed mechanism beyond the fact the flip requires a protonation state change of the DFG-Asp remains elusive. By using continuous constant pH molecular dynamics (CpHMD) with pH replica exchange, we investigated the activation mechanism of a Src kinase. The data revealed how DFG-flip is dependent on the pH conditions and showed intermediate states that could be used to design kinase inhibitors. The work demonstrates how CpHMD can help advance our understanding of pH-dependent structure-function relationships and accelerate drug design for kinases.<br/>

Unbiased kinase DFG-flip revealed by continuous constant pH molecular dynamics

2019 Spring National Meeting

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