title: Computational design of protein-small molecule interfaces.
abstract: The computational design of proteins that bind small molecule ligands is one of the unsolved challenges in protein engineering. It is complicated by the relatively small size of the ligand which limits the number of intermolecular interactions. Furthermore, near-perfect geometries between interacting partners are required to achieve high binding affinities. For apolar, rigid small molecules the interactions are dominated by short-range van der Waals forces. As the number of polar groups in the ligand increases, hydrogen bonds, salt bridges, cation-π, and π-π interactions gain importance. These partial covalent interactions are longer ranged, and additionally, their strength depends on the environment (e.g. solvent exposure). To assess the current state of protein-small molecule interface design, we benchmark the popular computer algorithm Rosetta on a diverse set of 43 protein-ligand complexes. On average, we achieve sequence recoveries in the binding site of 59% when the ligand is allowed limited reorientation, and 48% when the ligand is allowed full reorientation. When simulating the redesign of a protein binding site, sequence recovery among residues that contribute most to binding was 52% when slight ligand reorientation was allowed, and 27% when full ligand reorientation was allowed. As expected, sequence recovery correlates with ligand displacement.
authors: Department of Chemistry, 7330 Stevenson Center, Station B 351822, Nashville, TN 37235, USA.
authors: Brittany
authors: B
authors: Allison
authors: Department of Chemistry, 7330 Stevenson Center, Station B 351822, Nashville, TN 37235, USA.
authors: Steven
authors: S
authors: Combs
authors: Chemical and Physical Biology Program, 340 Light Hall, Nashville, TN 37232, USA.
authors: Sam
authors: S
authors: DeLuca
authors: Chemical and Physical Biology Program, 340 Light Hall, Nashville, TN 37232, USA.
authors: Gordon
authors: G
authors: Lemmon
authors: Department of Biochemistry, 607 Light Hall, Nashville, TN 37232, USA; Center for Structural Biology, 465 21st Avenue South, Nashville, TN 37232, USA.
authors: Laura
authors: L
authors: Mizoue
authors: Department of Chemistry, 7330 Stevenson Center, Station B 351822, Nashville, TN 37235, USA; Chemical and Physical Biology Program, 340 Light Hall, Nashville, TN 37232, USA; Department of Pharmacology, 476 Robinson Research Building, 2220 Pierce Avenue, Nashville, TN 37232, USA; Department of Biomedical Informatics, 400 Eskind Biomedical Library, 2209 Garland Ave, Nashville, TN 37232, USA; Center for Structural Biology, 465 21st Avenue South, Nashville, TN 37232, USA; Institute for Chemical Biology, 896 Preston Research Building, Nashville, TN 37232, USA. Electronic address: jens@meilerlab.org.
authors: Jens
authors: J
authors: Meiler
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D015202:Protein Engineering; D011506:Proteins / Q000737:chemistry*; D012984:Software
chemical_list: D008024:Ligands; D011506:Proteins
keywords: Computational interface design; Ligand docking; Protein-small molecule interaction; Rosetta; RosettaLigand; Sequence optimization
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