title: Interfacial folding and membrane insertion of designed peptides studied by molecular dynamics simulations.
abstract: The mechanism of interfacial folding and membrane insertion of designed peptides is explored by using an implicit membrane generalized Born model and replica-exchange molecular dynamics. Folding/insertion simulations initiated from fully extended peptide conformations in the aqueous phase, at least 28 A away from the membrane interface, demonstrate a general mechanism for structure formation and insertion (when it occurs). The predominately hydrophobic peptides from the synthetic WALP and TMX series first become localized at the membrane-solvent interface where they form significant helical secondary structure via a helix-turn-helix motif that inserts the central hydrophobic residues into the membrane interior, and then fluctuations occur that provide a persistent helical structure throughout the peptide and it inserts with its N-terminal end moving across the membrane. More specifically, we observed that: (i) the WALP peptides (WALP16, WALP19, and WALP23) spontaneously insert in the membrane as just noted; (ii) TMX-1 also inserts spontaneously after a similar mechanism and forms a transmembrane helix with a population of approximately 50% at 300 K; and (iii) TMX-3 does not insert, but exists in a fluctuating membrane interface-bound form. These findings are in excellent agreement with available experimental data and demonstrate the potential for new implicit solvent/membrane models together with advanced simulation protocols to guide experimental programs in exploring the nature and mechanism of membrane-associated folding and insertion of biologically important peptides.
authors.affiliation: Department of Molecular Biology (TPC6) and Center for Theoretical Biological Physics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Wonpil
authors.initials: W
authors.lastname: Im
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D006860:Hydrogen Bonding; D008566:Membranes / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D011392:Proline / Q000737:chemistry; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012984:Software; D013696:Temperature; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D010455:Peptides; D011392:Proline