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 "cutoff" switching distance of 0.4 nm was used because the average equivalent VDW radius of a residue is roughly 0.4 nm in coarse-grained models. Therefore, the close packing between two residues requires the distance to be smaller than 0.4 nm. For example, S = 0.8 indicates that the average minimal distance between any proline in P10 to W3, Y6, Y139 from PFN1 is 0.52 nm. Figure S2 shows that aromatic-proline stacking reaches the highest strength when P10 is close to PFN1 with a step function type of behavior. Combining Figure 3 and Figure S2 , we observed a concerted formation of hydrogen bonds and aromatic-proline stacking when P10 approaches PFN1. This "zipping" mechanism is reproducible with two different binding modes for the crystal binding pocket: mode9 ( Figure 3 ) and mode11 ( Figure S1 ). Thus, in addition to the conventional aromatic-proline interaction dominated mechanism, we demonstrated that hydrogen bonds between PFN1 residues (serines, tyrosines and tryptophans) and prolines also contribute significantly to the interactions, thus resulting in a "zipping" mechanism. Such observation also helps to explain the "anomaly" of the hydrophobicity of prolines discussed before 22 .