Molecular dynamics simulations of proteins in lipid bilayers

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With recent advances in X-ray crystallography of membrane proteins promising many new high-resolution structures, molecular dynamics simulations will become increasingly valuable for understanding membrane protein function, as they can reveal the dynamic behavior concealed in the static structures. Dramatic increases in computational power, in synergy with more efficient computational methodologies, now allow us to carry out molecular dynamics simulations of any structurally known membrane protein in its native environment, covering timescales of up to 0.1 μs. At the frontiers of membrane protein simulations are ion channels, aquaporins, passive and active transporters, and bioenergetic proteins.

Introduction

The successful solution of membrane protein structures permits molecular dynamics (MD) investigations to elucidate the physical mechanisms behind manifold processes associated with cellular membranes. The membrane environment influences the function of membrane proteins, through electrostatic and steric interactions as well as through the membrane's internal pressure. Therefore, the environment needs to be properly taken into account in MD studies. The resulting calculations, incorporating proteins, lipid bilayer, water and ions, need to cover between 50 000 atoms for the smallest proteins and up to 300 000 atoms for the largest one yet studied. The large simulation volume poses a major computational challenge; however, computational biologists have recently succeeded in carrying out the required calculations, and have been rewarded with discoveries and insights into the physical mechanisms underlying membrane processes. Here, we review selectively the reported investigations, focusing largely only on MD simulations that describe integral membrane proteins in realistic lipid bilayers. Figure 1 compares some of the membrane proteins covered in the simulations reviewed: two single-channel proteins (bacteriorhodopsin and KcsA), two multichannel proteins (aquaporin and OmpF) and a large multimeric channel, MscS. Presently, the structure/function relationships of membrane proteins are not well understood and there are great opportunities for new fundamental insight. It is likely that MD simulations will play a key role in realizing this potential. Indeed, the examples presented below reveal already significant successes.

Section snippets

Ion channels

Ion channels present a unique and difficult challenge for MD. Although appearing simpler than channels that transport small solutes, they are in some ways more complicated because of the very precise electrostatic interactions required between ion, protein and solvent. This highlights the need for exact force-field parameters to produce accurate results. As in many MD simulations, the difference between the timescale available to simulations and the timescale needed to calculate experimentally

Other selective channels

In addition to ions, living organisms have evolved channels that provide selective pathways for the passive permeation of other substrates. It has been suggested that cells have selective channels for the permeation of certain nutrient molecules, such as glycerol, gas molecules and even water. The best-known family of such channels is the membrane water channels known as aquaporins (AQPs). The solved structures of several AQPs at high resolution are indicative of the conserved protein

Non-selective channels and outer membrane proteins

Non-selective membrane channels facilitate the passive permeation of ions and other small solutes through lipid bilayers, selecting for permeation only those solutes that fit geometrically into the channel pore. Although referred to here as non-selective, most of the channels in this class exhibit minor to moderate selectivity for either cations or anions. Three types of non-selective channels are discussed below: mechanosensitive (MS) channels, pore-forming toxins and outer membrane porins.

Membrane proteins in bioenergetics and vision

Cellular energy is largely stored and used by membrane proteins in the form of a proton gradient across cellular membranes. The most prominent protein of this type is F1Fo-ATP synthase, which converts the membrane potential into chemical energy stored in ATP. ATP synthases link a mechanochemical motor, the F1 sector, to an electromechanical motor, the Fo sector. F1 couples the reaction ADP + phosphate ↔ ATP to mechanical torque, which acts on one of its rotating components, the stalk; Fo converts a

Conclusions

As expressed in the introduction, in situ MD simulations of membrane proteins have lived up to the opportunities that offer themselves today when structure analysis permits, for the first time, detailed glimpses into a molecular world that had been hidden before. Modeling can add tremendous value to newly resolved structures. An example is the mechanosensitive channel MscS: crystallography revealed an open channel, but MD simulation makes it more likely that the structure seen is actually only

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by the National Institutes of Health (PHS-5-P41-RR05969). The authors also gladly acknowledge computer time provided by the Pittsburgh Supercomputer Center and the National Center for Supercomputing Applications through the National Resources Allocation Committee (MCA93S028).

References (63)

  • G. Patargias et al.

    Molecular dynamics simulations of GlpF in a micelle vs in a bilayer: conformational dynamics of a membrane protein as a function of environment

    J Phys Chem B

    (2005)
  • P. Grayson et al.

    Mechanisms of selectivity in channels and enzymes studied with interactive molecular dynamics

    Biophys J

    (2003)
  • F. Zhu et al.

    Pressure-induced water transport in membrane channels studied by molecular dynamics

    Biophys J

    (2002)
  • Wang Y, Schulten K, Tajkhorshid E: What makes an aquaporin a glycerol channel: a comparative study of AqpZ and GlpF....
  • J. Gullingsrud et al.

    Gating of MscL studied by steered molecular dynamics

    Biophys J

    (2003)
  • G. Colombo et al.

    Simulation of MscL gating in a bilayer under stress

    Biophys J

    (2003)
  • A. Aksimentiev et al.

    Imaging alpha-hemolysin with molecular dynamics: ionic conductance, osmotic permeability and the electrostatic potential map

    Biophys J

    (2005)
  • W. Im et al.

    Ions and counterions in a biological channel: a molecular dynamics study of OmpF porin from Escherichia coli in an explicit membrane with 1 M KCl aqueous salt solution

    J Mol Biol

    (2002)
  • K.M. Robertson et al.

    Orientation and interactions of dipolar molecules during transport through OmpF porin

    FEBS Lett

    (2002)
  • M. Ceccarelli et al.

    Microscopic mechanism of antibiotics translocation through a porin

    Biophys J

    (2004)
  • P.J. Bond et al.

    OmpA: a pore or not a pore? Simulation and modeling studies

    Biophys J

    (2004)
  • P.J. Bond et al.

    Membrane protein dynamics versus environment: simulations of OmpA in a micelle and in a bilayer

    J Mol Biol

    (2003)
  • M. Baaden et al.

    A molecular dynamics investigation of mono and dimeric states of the outer membrane enzyme OMPLA

    J Mol Biol

    (2003)
  • J.D. Faraldo-Gómez et al.

    Molecular dynamics simulations of the bacterial outer membrane protein FhuA: a comparative study of the ferrichrome-free and bound states

    Biophys J

    (2004)
  • T. Meier et al.

    Structure of the rotor ring of F-type Na+-ATPase from Ilyobacter tartaricus

    Science

    (2005)
  • T. Murata et al.

    Structure of the rotor of the V-type Na+-ATPase from Enterococcus hirae

    Science

    (2005)
  • F. Autenrieth et al.

    Role of water in transient cytochrome c2 docking

    J Phys Chem B

    (2004)
  • H. Jang et al.

    How environment supports a state: molecular dynamics simulations of two states in bacteriorhodopsin suggest lipid and water compensation

    Biophys J

    (2004)
  • S. Grudinin et al.

    Water molecules and hydrogen-bonded networks in bacteriorhodopsin-molecular dynamics simulations of the ground state and the M-intermediate

    Biophys J

    (2005)
  • A. Onufriev et al.

    Proton affinity changes driving unidirectional proton transport in the bacteriorhodopsin photocycle

    J Mol Biol

    (2003)
  • T. Huber et al.

    Membrane model for the G-protein-coupled receptor rhodopsin: hydrophobic interface and dynamical structure

    Biophys J

    (2004)

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