title: Tryptophan side chain electrostatic interactions determine edge-to-face vs parallel-displaced tryptophan side chain geometries in the designed beta-hairpin "trpzip2".
abstract: The interaction geometries of the four tryptophan (Trp) side chains in the 12-residue designed beta-hairpin trpzip2 are investigated using all-atom explicit-solvent molecular dynamics simulations. The experimentally observed edge-to-face (EtF) pairwise interaction geometries are stable on a time scale of 10 ns. However, removing the electrostatic multipoles of the Trp side chains while retaining the dipoles of the side chains' NH moieties induces a conformational change to a geometry in which three of the four side chains interact in a parallel-displaced (PD) manner. Free energy simulations of the Etf to PD conformational change reveal that, with the side chain multipole moments intact (+MP), the EtF conformation is preferred by 5.79 kcal/mol. Conversely, with only the dipole moments of the side chain NH moieties intact (-MP), the PD conformation's free energy is more favorable by 1.71 kcal/mol. In contrast to energetic similarities for Trp side chain-water electrostatic and Trp side chain-Trp side chain and Trp side chain-water van der Waals, +MP Trp side chain-Trp side chain electrostatic interactions are more favorable by 4.21 kcal/mol in the EtF conformation, while in the -MP case the EtF and PD conformations' Trp side chain-Trp side chain electrostatic energies are nearly identical. The results highlight the importance of electrostatic multipole moments in determining aromatic-aromatic interaction geometries in aqueous biomolecular systems and argue for the inclusion of this physics in simplified models used for protein-ligand docking and protein structure prediction, possibly through a truncated Coulomb term between aromatic moieties.
authors.affiliation: Department of Molecular Biology (TPC-6), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Olgun
authors.initials: O
authors.lastname: Guvench
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks
mesh_terms: D003198:Computer Simulation; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D055672:Static Electricity; D013816:Thermodynamics; D014364:Tryptophan / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D010455:Peptides; D014867:Water; D014364:Tryptophan