Abstract
Protein–ligand binding is essential to almost all life processes. The understanding of protein–ligand interactions is fundamentally important to rational drug and protein design. Based on large scale data sets, we show that protein rigidity strengthening or flexibility reduction is a mechanism in protein–ligand binding. Our approach based solely on rigidity is able to unveil a surprisingly apparently long-range contribution of apparently four residue layers to protein–ligand binding, which has ramifications for drug and protein design. Additionally, the present work reveals that among various pairwise interactions, the short-range ones within the distance of the van der Waals diameter are most important. It is found that the present approach outperforms all other state-of-the-art scoring functions for protein–ligand binding affinity predictions of two benchmark test sets.
Duc Nguyen
Associate Professor of Mathematics
Duc Nguyen develops mathematical and AI frameworks for molecular bioscience, drug discovery, and scientific computing. His group blends differential geometry, graph theory, and machine learning to build high-fidelity models for biomolecular systems, with notable wins in the D3R Grand Challenges and collaborations with Pfizer and Bristol Myers Squibb. Supported by multiple NSF awards, he has advised students and postdocs across theory and applications of AI-driven drug design.