jp710964x - 13070 J. Phys. Chem. B 2008, 112, 1307013078...

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Dynamic Mechanism of Fatty Acid Transport across Cellular Membranes through FadL: Molecular Dynamics Simulations Hanjun Zou, Mingyue Zheng, Xiaomin Luo, Weiliang Zhu, Kaixian Chen, Jianhua Shen,* ,†,‡ and Hualiang Jiang* ,†,‡ Drug Disco V ery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China, and School of Pharmacy, East China Uni V ersity of Science and Technology, Shanghai 200237, China Recei V ed: No V ember 17, 2007; Re V ised Manuscript Recei V ed: May 17, 2008 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-af±nity site (HAS) from a low-af±nity 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 identi±ed nine possible pathways for dodecanoic acid (DA) threading the barrel of FadL. The binding free energy pro±les 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. Introduction Exogenous long-chain fatty acids (LCFAs) are sources of energy and carbon for many biological functions and biomol- ecule syntheses for both microorganisms and mammals. 1 - 4 In addition, the uptake of LCFAs might also be important to some pathophysiological processes such as bacterial infection. 5 There- fore, the transport of LCFAs across cellular membranes represents a fundamental biological process. 6 LCFAs can cross membranes spontaneously because of their hydrophobic nature. 6 However, in many prokaryotic and eukaryotic cells, the transport of exogenous LCFAs is effectively mediated by speci±c membrane-bound proteins. 7 So far, several distinct membrane- bound and membrane-associated fatty acid transport proteins have been identi±ed and characterized in a number of different
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This note was uploaded on 12/13/2010 for the course GENETIK 12 taught by Professor Atillabasar during the Spring '10 term at Istanbul Technical University.

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jp710964x - 13070 J. Phys. Chem. B 2008, 112, 1307013078...

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