Exploring the binding mechanism between human profilin (PFN1) and polyproline-10 through binding mode screening

Abstract

The large magnitude of protein-protein interaction (PPI) pairs within the human interactome necessitates the development of predictive models and screening tools to better understand this fundamental molecular communication. However, despite enormous efforts from various groups to develop predictive techniques in the last decade, PPI complex structures are in general still very challenging to predict due to the large number of degrees of freedom. In this study, we use the binding complex of human profilin (PFN1) and polyproline-10 (P10) as a model system to examine various approaches, with the aim of going beyond normal protein docking for PPI prediction and evaluation. The potential of mean force (PMF) was first obtained from the time-consuming umbrella sampling, which confirmed that the most stable binding structure identified by the maximal PMF difference is indeed the crystallographic binding structure. Moreover, crucial residues previously identified in experimental studies, W3, H133, and S137 of PFN1, were found to form favorable hydrogen bonds with P10, suggesting a zipping process during the binding between PFN1 and P10. We then explored both regular molecular dynamics (MD) and steered molecular dynamics (SMD) simulations, seeking for better criteria of ranking the PPI prediction. Despite valuable information obtained from conventional MD simulations, neither the commonly used interaction energy between the two binding parties nor the long-term root mean square displacement correlates well with the PMF results. On the other hand, with a sizable collection of trajectories, we demonstrated that the average and minimal rupture works calculated from SMD simulations correlate fairly well with the PMFs (R2 = 0.67), making this a promising PPI screening method.