Accurate free-energy calculations provide mechanistic insights into protein conformational equilibrium. In this talk, I will present free-energy calculations to study the thermodynamic properties of different conformations of Asp-Phe-Gly (DFG)-in/out in their equilibrium basin using the M2 algorithm. We used p38a mitogen-activated protein kinase (MAPK) as our test case. MAPKis a serine-threonine kinase which regulates the production of proinflammatory cytokines. The flexible DFG motif is closely connected to kinase activation and different inhibitor binding kinetics. Our calculations explain the coexistence of DFG-in and DFG-out states of the loop and reveal different components (e.g., configurational entropy and enthalpy) that stabilize the apo p38 a conformations. The non-polar spine residues in MAPK and the important role of the Gly residue in the DFG loop will also be discussed.

Insights from free energy calculations: DFG�in and �out conformational equilibrium and the driving forces

248th National Meeting (2014)

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