Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes (original) (raw)
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In this article, we provide an overview of lipid simulations, describing how a computer can be used as a laboratory for lipid research. We briefly discuss the methodology of lipid simulations followed by a number of topical applications that show the benefit of computer modeling for complementing experiments. In particular, we show examples of cases in which simulations have made predictions of novel phenomena that have later been confirmed by experimental studies. Overall, the applications discussed in this article focus on the most recent state of the art and aim to provide a perspective of where the field of lipid simulations stands at the moment.
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Biological membranes generate specific functions through compartmentalized regions such as cholesterol-enriched membrane nanodomains that host selected proteins. Despite the biological significance of nanodomains, details on their structure remain elusive. They cannot be observed via microscopic experimental techniques due to their small size, yet there is also a lack of atomistic simulation models able to describe spontaneous nanodomain formation in sufficiently simple but biologically relevant complex membranes. Here we use atomistic simulations to consider a binary mixture of saturated dipalmitoylphosphatidylcholine and cholesterol-the "minimal standard" for nanodomain formation. The simulations reveal how cholesterol drives the formation of fluid cholesterol-rich nanodomains hosting hexagonally packed cholesterol-poor lipid nanoclusters, both of which show registration between the membrane leaflets. The complex nanodomain substructure forms when cholesterol positions itself in the domain boundary region. Here cholesterol can also readily flip-flop across the membrane. Most importantly, replacing cholesterol with a sterol characterized by a less asymmetric ring region impairs the emergence of nanodomains. The model considered explains a plethora of controversial experimental results and provides an excellent basis for further computational studies on nanodomains. Furthermore, the results highlight the role of cholesterol as a key player in the modulation of nanodomains for membrane protein function.
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International Journal of Molecular Sciences, 2010
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Perspective: Computational modeling of accurate cellular membranes with molecular resolution
The Journal of Chemical Physics, 2018
Modeling lipid bilayers using molecular simulations has progressed from short simulations of single-component lipids to currently having the ability to model complex cellular membranes with nearly 100 different lipid types on a μs time scale. This perspective article presents a review of how the chemical physics field has provided insight into the structure and dynamics of accurate cellular membrane models. A short review of lipid force fields is presented, and how lower-resolution models can allow for assemblies and time scales not attainable with all-atom models. Key examples on membranes that mimic the lipid diversity seen in nature are provided for all-atom and coarse-grained lipid force fields. The article concludes with an outlook for the field on where there exist certain challenges (lipid diversity and leaflet concentration asymmetry) over the next several years. This is an exciting time to be a researcher in the field of modeling cellular membranes with ultimate goals to mo...
Journal of Physics Condensed Matter, 2006
We have reparameterized the dihedral parameters in a commonly used unitedatom lipid force field so that they can be used with the all-atom OPLS force field for proteins implemented in the molecular dynamics simulation software GROMACS. Simulations with this new combination give stable trajectories and sensible behaviour of both lipids and protein. We have calculated the free energy of transfer of amino acid side chains between water and 'lipidcyclohexane', made of lipid force field methylene groups, as a hydrophobic mimic of the membrane interior, for both the OPLS-AA and a modified OPLS-AA force field which gives better hydration free energies under simulation conditions close to those preferred for the lipid force field. The average error is 4.3 kJ mol −1 for water-'lipid-cyclohexane' compared to 3.2 kJ mol −1 for OPLS-AA cyclohexane and 2.4 kJ mol −1 for the modified OPLS-AA water-'lipid-cyclohexane'. We have also investigated the effect of different methods to combine parameters between the united-atom lipid force field and the unitedatom protein force field ffgmx. In a widely used combination, the strength of interactions between hydrocarbon lipid tails and proteins is significantly overestimated, causing a decrease in the area per lipid and an increase in lipid ordering. Using straight combination rules improves the results. Combined, we suggest that using OPLS-AA together with the united-atom lipid force field implemented in GROMACS is a reasonable approach to membrane protein simulations. We also suggest that using partial volume information and free