title: Melittin Aggregation in Aqueous Solutions: Insight from Molecular Dynamics Simulations.
abstract: Melittin is a natural peptide that aggregates in aqueous solutions with paradigmatic monomer-to-tetramer and coil-to-helix transitions. Since little is known about the molecular mechanisms of melittin aggregation in solution, we simulated its self-aggregation process under various conditions. After confirming the stability of a melittin tetramer in solution, we observed—for the first time in atomistic detail—that four separated melittin monomers aggregate into a tetramer. Our simulated dependence of melittin aggregation on peptide concentration, temperature, and ionic strength is in good agreement with prior experiments. We propose that melittin mainly self-aggregates via a mechanism involving the sequential addition of monomers, which is supported by both qualitative and quantitative evidence obtained from unbiased and metadynamics simulations. Moreover, by combining computer simulations and a theory of the electrical double layer, we provide evidence to suggest why melittin aggregation in solution likely stops at the tetramer, rather than forming higher-order oligomers. Overall, our study not only explains prior experimental results at the molecular level but also provides quantitative mechanistic information that may guide the engineering of melittin for higher efficacy and safety.
authors.affiliation: †Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States.
authors.forename: Chenyi
authors.initials: C
authors.lastname: Liao
authors.affiliation: ‡Schrödinger, Inc., 120 West 45th Street, 17th Floor, New York, New York 10036, United States.
authors.forename: Myvizhi
authors.initials: M
authors.lastname: Esai Selvan
authors.affiliation: §National Institute of Deafness and Other Communication Disorders, Bethesda, Maryland 20892, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: †Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Slimovitch
authors.affiliation: †Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States.
authors.forename: Severin T
authors.initials: ST
authors.lastname: Schneebeli
authors.affiliation: ∥Schrödinger, Inc., 101 SW Main Street, Suite 1300, Portland, Oregon 97204, United States.
authors.forename: Mee
authors.initials: M
authors.lastname: Shelley
authors.affiliation: ∥Schrödinger, Inc., 101 SW Main Street, Suite 1300, Portland, Oregon 97204, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Shelley
authors.affiliation: †Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States.
authors.forename: Jianing
authors.initials: J
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D019281:Dimerization; D008555:Melitten / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009994:Osmolar Concentration; D066329:Protein Aggregates; D017433:Protein Structure, Secondary; D012996:Solutions; D013696:Temperature; D014867:Water / Q000737:chemistry*
chemical_list: D066329:Protein Aggregates; D012996:Solutions; D014867:Water; D008555:Melitten