Peptide folding and partitioning in translocon-like pores: a molecular dynamics study

translocon;SecY;lateral gate;membrane protein;molecular dynamics;OPLS;protein folding;Materials Science & Engineering

Fennell, Hayden WilliamUlmschneider, Martin B. ;

Johns Hopkins University

关键词: translocon;    SecY;    lateral gate;    membrane protein;    molecular dynamics;    OPLS;    protein folding;    Materials Science & Engineering;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/38086/FENNELL-THESIS-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

The protein transport apparatus (or ;;translocon”) is a critical component of cellular operation in all three domains of life. Responsible for transporting a wide variety of proteins both through and across cell membranes, the translocon is one of the most important biological nanopores found in nature. Although recent crystal structure analysis has revealed much about the structure and behavior of the translocon, many of the mechanisms driving its function remain poorly understood. Particularly mysterious among these unknowns is the ;;lateral gating” process: the selective lateral partitioning of folded transmembrane helices into the membrane through a gate-like opening on the side of the translocon. In the following study, molecular dynamics simulations are used to investigate the process of protein folding and partitioning within a simplified model of the translocon channel geometry. Relatively recent crystallographic structures of the bacterial SecY translocon reveal that the translocon assumes an hourglass shape with a narrow constriction in the center of the pore that is thought to both direct the transport of secretory proteins and aid in the rapid folding of helical transmembrane segments. Our theoretical model allows for the systematic variation of multiple key features of the channel, namely the level of constriction around the peptide, the hydration and polarity of the pore, and the state of the lateral gate (open/closed). The influence of these features on folding within the channel is tested using a 27-residue hydrophobic peptide that has been shown to be preferentially inserted into membranes by the translocon. Open gate models are also used to investigate the partitioning behavior of these helices once the chain has folded and the lateral gate has opened. Our results demonstrate that both the polarity of the channel and the magnitude of constraint imposed by the central constriction are determining factors of peptide folding within the translocon, and that protein partitioning through the lateral gate may require long timescales in comparison to the rate of folding.