Dynamic Mechanism of Fatty Acid Transport across Cellular Membranes through FadL:
Molecular Dynamics Simulations
and Hualiang Jiang*
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
ersity of Science and Technology, Shanghai 200237, China
ember 17, 2007; Re
ised Manuscript Recei
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.
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.
addition, the uptake of LCFAs might also be important to some
pathophysiological processes such as bacterial infection.
fore, the transport of LCFAs across cellular membranes
represents a fundamental biological process.
LCFAs can cross
membranes spontaneously because of their hydrophobic nature.
However, in many prokaryotic and eukaryotic cells, the transport
of exogenous LCFAs is effectively mediated by speci±c
So far, several distinct membrane-
bound and membrane-associated fatty acid transport proteins
have been identi±ed and characterized in a number of different