title: Impact of Surface Water Layers on Protein--Ligand Binding: How Well Are Experimental Data Reproduced by Molecular Dynamics Simulations in a Thermolysin Test Case?
abstract: Drug binding involves changes of the local water structure around proteins including water rearrangements across surface-solvation layers around protein and ligand portions exposed to the newly formed complex surface. For a series of thermolysin-binding phosphonamidates, we discovered that variations of the partly exposed P2'-substituents modulate binding affinity up to 10 kJ mol(-1) with even larger enthalpy/entropy partitioning of the binding signature. The observed profiles cannot be completely explained by desolvation effects. Instead, the quality and completeness of the surface water network wrapping around the formed complexes provide an explanation for the observed structure-activity relationship. We used molecular dynamics to compute surface water networks and predict solvation sites around the complexes. A fairly good correspondence with experimental difference electron densities in high-resolution crystal structures is achieved; in detail some problems with the potentials were discovered. Charge-assisted contacts to waters appeared as exaggerated by AMBER, and stabilizing contributions of water-to-methyl contacts were underestimated.
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Betz
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Wulsdorf
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Krimmer
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
mesh_terms: D015195:Drug Design; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013820:Thermolysin / Q000737:chemistry / Q000378:metabolism*; D014867:Water / Q000737:chemistry*
chemical_list: D008024:Ligands; D014867:Water; D013820:Thermolysin