Free Energy Barriers for the N-Terminal Asparagine to Succinimide Conversion: Quantum Molecular Dynamics Simulations for the Fully Solvated Model

Deamidation of asparagine residues represents one of the main routes for the post-translational modification of protein sequences. We computed the estimates of the free energy barriers for three stages of the deamidation process, deprotonation, cyclization, and deamination, of the conversion of asparagine to the succinimide intermediate within the fully solvated model with explicit water molecules. The Born-Oppenheimer molecular dynamics in the Gaussian and Plane Wave (GPW) approximation as implemented in the CP2K quantum chemistry package was utilized to sample the configurational space. By applying the metadynamics technique, the estimates of the free energy barriers were obtained for three separated stages of the reaction. In agreement with the experimental kinetic measurements, the estimated activation barriers do not exceed 21 kcal/mol. We demonstrate that the use of fully solvated models is the critical issue in theoretical studies of these reactions. We also conclude that more extensive sampling is necessary to obtain full free energy profiles and accurate barriers for the reaction stages.