Improving the predictive performance of binding affinities and poses for protein-cyclic peptide complexes through fine-tuned MM/PBSA(GBSA)-based methods.

Cyclic peptides represent a highly promising class of biopharmaceutical scaffolds. The screening of cyclic peptides against protein targets can be greatly facilitated using computational approaches, especially molecular docking. However, it remains a crucial challenge to accurately predict protein-cyclic peptide (P-cp) interactions employing scoring functions of molecular docking. End-point approaches, such as molecular mechanics generalized Born surface area (MM/GBSA) and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA), provide theoretically more robust frameworks than conventional scoring functions, but their reliability in predicting binding affinities and discriminating native-like binding poses for P-cp complexes remains poorly quantified. Herein, we comprehensively assessed the predictive abilities of MM/PBSA(GBSA) in scoring binding affinities of P-cp complexes and re-ranking their binding poses. The binding affinity scoring ability of MM/PBSA(GBSA) was assessed on a carefully curated dataset consisting of 50 complexes involving P-cp binding affinities, and their re-ranking capability was evaluated on another dataset consisting of the decoys of 81 P-cp complexes. Based on these assessments, we proposed a two-step workflow for predicting P-cp binding affinities. First, we employed the assessed optimal re-ranking method to select the top-1 binding pose; second, we estimated the binding affinity based on the selected top-1 pose using the assessed optimal scoring method. Our proposed workflow, which requires only 3 s for each prediction, achieves binding affinity predictions with a Rp of -0.732 when compared to experimental values, which is twice as high as that of AutoDock CrankPep (Rp = -0.316). This study emphasizes the necessity of using fine-tuned MM/PBSA(GBSA) methods for predicting P-cp interactions.