title: Dynamic mechanism of fatty acid transport across cellular membranes through FadL: molecular dynamics simulations.
abstract: FadL is an important member of the family of fatty acid transport proteins within membranes. In this study, 11 conventional molecular dynamics (CMD) and 25 steered molecular dynamics (SMD) simulations were performed to investigate the dynamic mechanism of transport of long-chain fatty acids (LCFAs) across FadL. The CMD simulations addressed the intrinsically dynamic behavior of FadL. Both the CMD and SMD simulations revealed that a fatty acid molecule can move diffusively to a high-affinity site (HAS) from a low-affinity site (LAS). During this process, the swing motion of the L3 segment and the hydrophobic interaction between the fatty acid and FadL could play important roles. Furthermore, 22 of the SMD simulations revealed that fatty acids can pass through the gap between the hatch domain and the transmembrane domain (TMD) by different pathways. SMD simulations identified nine possible pathways for dodecanoic acid (DA) threading the barrel of FadL. The binding free energy profiles between DA and FadL along the MD trajectories indicate that all of the possible pathways are energetically favorable for the transport of fatty acids; however, one pathway (path VI) might be the most probable pathway for DA transport. The reasonability and reliability of this study were further demonstrated by correlating the MD simulation results with the available mutagenesis results. On the basis of the simulations, a mechanism for the full-length transport process of DA from the extracellular side to the periplasmic space mediated by FadL is proposed.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, China.
authors.forename: Hanjun
authors.initials: H
authors.lastname: Zou
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D001692:Biological Transport; D002462:Cell Membrane; D003198:Computer Simulation; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism; D050612:Fatty Acid Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D007850:Lauric Acids / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D019897:Periplasm / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013997:Time Factors
chemical_list: D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D007850:Lauric Acids; C065691:fadL protein, E coli; C030358:lauric acid