A molecular dynamics investigation of the kinetic bottlenecks of the hPin1 WW domain. I: simulations with the Sorenson/Head-Gordon model

The availability of a large amount of experimental data makes the Pin1 WW domain an ideal benchmark to test computational methods. The purpose of the present work is to identify the kinetic bottlenecks of the folding/unfolding pathway through Molecular Dynamics simulations. In this paper, the first of the series, we use the Sorenson/Head-Gordon model, based on the hydrophobicity properties of the chain residues. The unfolding simulation shows a highly cooperative mechanism that correctly identifies the contacts of loop I as the kinetic bottlenecks, in agreement with the ?-value analysis performed by Gruebele et al.. The folding simulation, on the other hand, proves to be able to capture the essential topological features of the native fold even if the Kabsch distance from the PDB structure is still rather high. In the second paper of the series we report on simulations within the frame of the Go model, and the performances of the two models are compared and discussed.