title: Calculation of configurational entropy with a Boltzmann-quasiharmonic model: the origin of high-affinity protein-ligand binding.
abstract: Accurate assessment of configurational entropy remains a large challenge in biology. While many methods exist to calculate configurational entropy, there is a balance between accuracy and computational demands. Here we calculate ligand and protein conformational entropies using the Boltzmann-quasiharmonic (BQH) method, which treats the first-order entropy term by the Boltzmann expression for entropy while determining correlations using the quasiharmonic model. This method is tested by comparison with the exact Clausius expression for entropy on a range of test molecules ranging from small ligands to a protein. Using the BQH method, we then analyze the rotational and translational (R/T) entropy change upon ligand binding for five protein complexes to explore the origins of extremely tight affinity. The results suggest that in these systems such affinity is achieved by a combination of simultaneously maintaining good protein-ligand contacts while allowing significant residual R/T motion of the ligand through suitable protein motions.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Harpole
authors.forename: Kim A
authors.initials: KA
authors.lastname: Sharp
mesh_terms: D019277:Entropy; D008024:Ligands; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013696:Temperature
chemical_list: D008024:Ligands; D011506:Proteins