title: Multidimensional umbrella sampling and replica-exchange molecular dynamics simulations for structure prediction of transmembrane helix dimers.
abstract: Structural information of a transmembrane (TM) helix dimer is useful in understanding molecular mechanisms of important biological phenomena such as signal transduction across the cell membrane. Here, we describe an umbrella sampling (US) scheme for predicting the structure of a TM helix dimer in implicit membrane using the interhelical crossing angle and the TM-TM relative rotation angles as the reaction coordinates. This scheme conducts an efficient conformational search on TM-TM contact interfaces, and its robustness is tested by predicting the structures of glycophorin A (GpA) and receptor tyrosine kinase EphA1 (EphA1) TM dimers. The nuclear magnetic resonance (NMR) structures of both proteins correspond to the global free-energy minimum states in their free-energy landscapes. In addition, using the landscape of GpA as a reference, we also examine the protocols of temperature replica-exchange molecular dynamics (REMD) simulations for structure prediction of TM helix dimers in implicit membrane. A wide temperature range in REMD simulations, for example, 250-1000 K, is required to efficiently obtain a free-energy landscape consistent with the US simulations. The interhelical crossing angle and the TM-TM relative rotation angles can be used as reaction coordinates in multidimensional US and be good measures for conformational sampling of REMD simulations.
authors.affiliation: RIKEN Research Center for Allergy and Immunology (RCAI), 1-7-22 Suehiro-cho, Tsurumi-ku,Yokohama, Kanagawa, 230-0045, Japan; RIKEN Theoretical Molecular Science Laboratory, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
authors.forename: Pai-Chi
authors.initials: PC
authors.lastname: Li
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miyashita
authors.forename: Wonpil
authors.initials: W
authors.lastname: Im
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sugita
mesh_terms: D006021:Glycophorins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D055503:Protein Multimerization; D036082:Receptor, EphA1 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006021:Glycophorins; D036082:Receptor, EphA1
keywords: REMD; glycophorin A; receptor tyrosine kinase EphA1; structure prediction; transmembrane helix dimer; umbrella sampling