Molecular dynamics simulations of proteins in lipid bilayers
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).
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