title: Peptide Folding in Translocon-Like Pores.
abstract: The cellular translocon, present in all three domains of life, is one of the most versatile and important biological nanopores. This complex molecular apparatus is directly responsible for the secretion of globular proteins across membranes as well as the insertion of integral membrane proteins into lipid bilayers. Recently determined structures of the archaean SecY translocon reveal an hour-glass-shaped pore, which accommodates the nascent peptide chain during translocation. While these structures provide important insights into ribosome binding to the translocon, threading of the nascent chain into the channel, and lateral gate opening for releasing the folded helical peptide into the membrane bilayer, the exact folding pathway of the peptide inside the protein-conducting channel during translocation and prior to the lateral release into the bilayer remains elusive. In the present study, we use molecular dynamics simulations to investigate atomic resolution peptide folding in hour-glass-shaped pore models that are based on the SecY translocon channel structure. The theoretical setup allows systematic variation of key determinants of folding, in particular the degree of confinement of the peptide and the hydration level of the pore. A 27-residue hydrophobic peptide was studied that is preferentially inserted into membranes by the translocon. Our results show that both pore diameter as well as channel hydration are important determinants for folding efficiency and helical stability of the peptide, therefore providing important insights into translocon gating and lateral peptide partitioning.
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA, mulmsch1@jhu.edu.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Ulmschneider
authors.forename: Julia
authors.initials: J
authors.lastname: Koehler Leman
authors.forename: Hayden
authors.initials: H
authors.lastname: Fennell
authors.forename: Oliver
authors.initials: O
authors.lastname: Beckstein
mesh_terms: D000595:Amino Acid Sequence; D002135:Calcium-Binding Proteins / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry*; D008562:Membrane Glycoproteins / Q000737:chemistry*; D026901:Membrane Transport Proteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D017510:Protein Folding; D017433:Protein Structure, Secondary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D018000:Receptors, Peptide / Q000737:chemistry*
chemical_list: D002135:Calcium-Binding Proteins; D008051:Lipid Bilayers; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D010455:Peptides; D010713:Phosphatidylcholines; D018160:Receptors, Cytoplasmic and Nuclear; D018000:Receptors, Peptide; C066973:signal sequence receptor