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Trinity College Dublin

MOLecular DYnamics of Biological Membranes: Approaching the Mesoscale

MOLDY: An EU Transfer of Knowledge project.

Dr. Justine Taylor, School of Chemistry, Trinity College, Dublin

The lipid bilayer is a marvel of biological engineering. It is both rigid and flexible, impermeable and passive, a barrier and a container, in its own right. Membranes have been studied successfully on the macroscale for several decades. However, details of their full atomistic structure and function remain largely a mystery. Localised membrane compositions have been quantified and macroscopic properties studied over a range of conditions. The red cell membrane, for instance, is known to contain 52% protein, 40% lipid and 8% carbohydrate by weight {1} and undergoes a phase transition at, approximately, 17-25oC {2}. The liquid crystalline state (above the transition temperature) is the biologically relevant phase in which lipids adopt a disordered and fluid phase. Historically, the "fluid mosaic model" {3} has been used to define mesoscale membrane structure, whereby, proteins and lipids are thought to diffuse freely and randomly throughout the membrane plane (Figure 1).

Figure 1: The cell membrane. This figure has been taken from Wikimedia Commons (http://en.wikipedia.org/wiki/Image:Cell_membrane_detailed_diagram.svg) and is not under copywrite.

The diffusive nature of membranes is without contention, however, the identification of "lipids rafts" in the 1980's {4} suggests that microdomain structure is more common than not. The dynamic nature of the fluid phase means that capturing micro and mesoscale structural detail is experimentally difficult. Current atomistic imaging techniques rely on the generation of static structures over which data can be accumulated. Achieving this without destroying the fluid structure of the membrane or inducing a phase change is a challenge. It is in this regard that molecular dynamics has much to offer the field of membrane research. Over the past 15 years the field of membrane simulation has blossomed with simulations ranging from simple one component bilayers to large multi-component biological systems. The success of any such simulation, however, is determined by the ability of the implemented force field to define realistic atomistic behaviour. Proteins, water and many small molecules all have validated force field models and thus can be reliably simulated. For lipids, the case is less clear cut. United-atom models* have been defined and validated for several lipids and at this point represent the most reliable lipid force fields. Explicit all-atom models lag somewhat in that simulations utilizing current models have shown significant deviation from experimental behaviour. The development of a reliable all-atom lipid model would mean that full biological membrane systems could be defined and micro and mesoscale properties explored. The increasing amounts of computational power available to researchers will aid in defining progressively larger systems, with the goal of simulating multiple membrane microdomains in a single simulation.

Figure 2: A DPPC membrane immersed in a 0.2 M solution of NaCl. Solvent has been cut back to show membrane detail.

The initial phase of the MOLDY EU TOK project has been the validation of a new force field {5} for all-atom lipid simulations. An example of one of the resulting validated membrane systems is shown in Figure 2. The new force field allowed for the development of an accurate liquid crystalline phase, whereby, individual lipid molecules were free to move in the plane of the membrane. This is illustrated in Figure 3, where individual lipid headgroup movements (shown as different colours) were traced over time. The lower panel, with the improved force field, shows general diffusive behaviour whereas the top frame exhibits directional lipid movement, as is typical of the "gel" or ordered lipid phase.

As mentioned previously, the cell membrane contains a significant amount of protein. Proteins can be either fully embedded in the lipid bilayer (integral transmembrane), partially embedded (integral monotopic) or simply associated with the membrane surface (peripheral). Although all forms are key to cell functioning it is the integral transmembrane proteins that are most often the target of drug design campaigns. One such key family of proteins are the G-coupled protein receptor (GPCR) proteins which account for over 50% of the current human therapeutics market.{6} This family of proteins is stimulated by a wide range of extracellular signals and are key in relaying messages to intracellular components. The second phase of this project will aim to use the newly validated membrane systems in order to model full membrane/protein systems. An example of such a system is shown in Figure 4, where a GPCR has been embedded in a lipid bilayer. This mixing of proteins and lipids in the same simulation brings us a step closer to full cell membrane simulations.

* Models in which not all atoms are explicitly defined.

Figure 3: Lateral diffusion of individual lipids (shown as different colours) over time for the original force field (top) and the modified force field (bottom). Figure 4: GPCR embedded in a PDPC membrane and solvated in 0.2 M NaCl. Lipids and solvent has been cut back to show protein detail.

Acknowledgements This work is funded by the EU Marie Curie Transfer of Knowledge Programme. Resources were made available from the HEA PRTLI IITAC Programme.

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