biostudies-literatureUnknownZhou SNHGRI NIH HHSThere are continuous efforts to elucidate the structure and biological functions of short hydrogen bonds (SHBs), whose donor and acceptor heteroatoms reside more than 0.3 A closer than the sum of their van der Waals radii. In this work, we evaluate 1070 atomic-resolution protein structures and characterize the common chemical features of SHBs formed between the side chains of amino acids and small molecule ligands. We then develop a machine learning assisted prediction of protein-ligand SHBs (MAPSHB-Ligand) model and reveal that the types of amino acids and ligand functional groups as well as the sequence of neighboring residues are essential factors that determine the class of protein-ligand hydrogen bonds. The MAPSHB-Ligand model and its implementation on our web server enable the effective identification of protein-ligand SHBs in proteins, which will facilitate the design of biomolecules and ligands that exploit these close contacts for enhanced functions.Research squarers.3.rs-2895170https://www.ebi.ac.uk/biostudies/studies/S-EPMC10246099biostudies-literatureChemical Features and Machine Learning Assisted Predictions of Protein-Ligand Short Hydrogen Bonds.PMC10246099R01 HG007377Liu YZhou SWang SWang LfalseChemical Features and Machine Learning Assisted Predictions of Protein-Ligand Short Hydrogen Bonds.There are continuous efforts to elucidate the structure and biological functions of short hydrogen bonds (SHBs), whose donor and acceptor heteroatoms reside more than 0.3 A closer than the sum of their van der Waals radii. In this work, we evaluate 1070 atomic-resolution protein structures and characterize the common chemical features of SHBs formed between the side chains of amino acids and small molecule ligands. We then develop a machine learning assisted prediction of protein-ligand SHBs (MAPSHB-Ligand) model and reveal that the types of amino acids and ligand functional groups as well as the sequence of neighboring residues are essential factors that determine the class of protein-ligand hydrogen bonds. The MAPSHB-Ligand model and its implementation on our web server enable the effective identification of protein-ligand SHBs in proteins, which will facilitate the design of biomolecules and ligands that exploit these close contacts for enhanced functions.2023-01-01T00:00:00Z2023 May2025-04-04T10:21:48.847Z2025-02-19T02:38:03.182ZS-EPMC102460993729282210.21203/rs.3.rs-2895170/v1