Exploring the Binding Mechanism between Human Profilin (PFN1) and Polyproline-10 through Binding Mode Screening

Leili Zhang; David R. Bell; Binquan Luan; Ruhong Zhou

The crystal structure of PFN1-P10 has been determined by two independent experimental groups 20-21 , proving the benchmark for the predictive computational methods. Meanwhile a challenging aspect of this system is that proline has unusual solution properties, identified as an anomalous residue in terms of its hydrophobicity [22] [23] . Thus, PFN1-P10 provides us with two possible validation tests within one system. The first is to validate if the force field guided simulations are able to reproduce experimental findings. We conducted free energy calculations to compare the crystal structure with the best structure predicted and also to investigate its associated binding mechanism. Along the latter line, we uncovered a zipping process during the binding of P10 with PFN1, highlighting the importance of W3, H133 and S137 of PFN1. The second is to examine MD simulations, steered molecular dynamics (SMD) simulations, and free energy calculations in comparison with the protein docking score (from GRAMM-X) in order to improve the ranking of docked structures and potentially go beyond protein-protein docking. We found that by following the protocol of using SMD simulation on the GRAMM-X docked structures, we were able to rank the relative stability of the PPI docked structures with reasonably high confidence.