Targeted molecular dynamics simulations of protein unfolding

The usefulness of targeted molecular dynamics (TMD) for the simulation of l arge conformational transitions is assessed in this work on the unfolding p rocess of chymotrypsin inhibitor 2 (CI2). In TMD the force field is supplem ented with a harmonic restraint which promotes either the increase of the c onformational distance from the native state or the decrease of the distanc e from a target unfolded structure. As a basis of comparison, unfolding is also simulated by conventional, i.e., unrestrained, molecular dynamics at 3 75 and 475 K. In all simulations, an implicit approximation of solvation is used to adiabatically model the solvent response, which is appropriate for the nanosecond unfolding simulation method used here. In total, 44 TMD and 25 unrestrained high-temperature molecular dynamics simulations of CI2 unf olding were performed with an implicit solvation model that allowed more th an 150 ns to be sampled. Qualitative agreement is found between the results of the TMD and unrestrained molecular dynamics at high temperature. The en ergies of the conformations sampled during TMD unfolding at 300 and 475 K a re comparable to the ones obtained by conventional molecular dynamics at 37 5 and 475 K, respectively. The sequence of events, i.e., secondary and tert iary structure disruption, is similar in all unfolding simulations, despite the diversity of the pathways. Previous simulations of CI2 performed with different force fields and solvation models showed a similar sequence of ev ents. This indicates that the TMD pathways are realistic even for very larg e conformational transitions such as protein unfolding.