Binding of Small-Molecule Ligands to Proteins: “What You See” Is Not Always “What You Get”

By David L. Mobley, Ken A. Dill. Structure, 2009

560 citations recorded by the source corpus.

We review insights from computational studies of affinities of ligands binding to proteins. The power of structural biology is in translating knowledge of protein structures into insights about their forces, binding, and mechanisms. However, the complementary power of computer modeling is in showing “the rest of the story” (i.e., how motions and ensembles and alternative conformers and the entropies and forces that cannot be seen in single molecular structures also contribute to binding affinities). Upon binding to a protein, a ligand can bind in multiple orientations; the protein or ligand can be deformed by the binding event; waters, ions, or cofactors can have unexpected involvement; and conformational or solvation entropies can sometimes play large and otherwise unpredictable roles. Computer modeling is helping to elucidate these factors.

Subfields: Computational Theory and Mathematics, Materials Chemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/75e498efffc664236bcd00cac7eb93b20c29d64b

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Citations in the corpus

Optimized Hydrophobic Interactions and Hydrogen Bonding at the Target-Ligand Interface Leads the Pathways of Drug-Designing (2010, background): “Hence, any small molecule that binds to a target loses its internal freedom, translational and rotational entropy [23].”
Alchemical free energy methods for drug discovery: Progress and challenges (2011, result): “This also makes it difficult to predict the experimentally resolved binding mode, as noted elsewhere [31 ,38,39].”
Enhancing structure prediction and design of soluble and membrane proteins with explicit solvent-protein interactions (2017, background): “However, implicit solvent approaches often lack accuracy in predicting and designing protein-protein, protein-ligand binding and protein catalysis which involve specific protein-solvent molecule interactions (Dragan et al., 2016; Lensink et al., 2014; Mobley and Dill, 2009; Sousa et al., 2006).”