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

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

In this paper we systematically study the PPI binding structures of PFN1-P10 using the protein docking program GRAMM-X, regular MD simulations, free energy methods (umbrella sampling) and SMD simulations, with the aim of going beyond normal protein docking for PPI prediction and evaluation. We demonstrate that the OPLS-AA force field guided umbrella sampling is able to identify the crystal structure as the most stable binding structure, which also appears in the top 10 list from GRAMM-X. Our comparative analysis shows that aromatic-proline stacking contributes the most to the stabilization of PFN1-P10 binding, along with the formation of hydrogen bonds between serines/tyrosines/tryptophans and prolines. Although regular MD simulations provide mixed information in terms of predicting the most stable binding structure, yet we find that 50 ns RMSDs might be useful with cautions for ranking the PPI prediction (see Supporting Information for details). On the other hand, SMD simulations provide a fast and All rights reserved. No reuse allowed without permission.