Systematic multiscale simulation of membrane protein systems

Ayton, Gary S.; Voth, Gregory A.

doi:10.1016/j.sbi.2009.03.001

Cited by 93 publications

(82 citation statements)

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“…Therefore, the use of fully atomistic methods is impractical. A number of CG models have been proposed to overcome this challenge (19)(20)(21)(22)(23). The MARTINI CG model (19,20) used here (Fig.…”

Section: Resultsmentioning

confidence: 99%

Organization, dynamics, and segregation of Ras nanoclusters in membrane domains

Janosi

Hancock

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

165

241

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Recent experiments have shown that membrane-bound Ras proteins form transient, nanoscale signaling platforms that play a crucial role in high-fidelity signal transmission. However, a detailed characterization of these dynamic proteolipid substructures by high-resolution experimental techniques remains elusive. Here we use extensive semiatomic simulations to reveal the molecular basis for the formation and domain-specific distribution of Ras nanoclusters. As model systems, we chose the triply lipidated membrane targeting motif of H-ras (tH) and a large bilayer made up of di16∶0-PC (DPPC), di18∶2-PC (DLiPC), and cholesterol. We found that 4-10 tH molecules assemble into clusters that undergo molecular exchange in the sub-μs to μs time scale, depending on the simulation temperature and hence the stability of lipid domains. Driven by the opposite preference of tH palmitoyls and farnesyl for ordered and disordered membrane domains, clustered tH molecules segregate to the boundary of lipid domains. Additionally, a systematic analysis of depalmitoylated and defarnesylated tH variants allowed us to decipher the role of individual lipid modifications in domain-specific nanocluster localization and thereby explain why homologous Ras isoforms form nonoverlapping nanoclusters. Moreover, the localization of tH nanoclusters at domain boundaries resulted in a significantly lower line tension and increased membrane curvature. Taken together, these results provide a unique mechanistic insight into how protein assembly promoted by lipid-modification modulates bilayer shape to generate functional signaling platforms.lipid bilayer | lipidated Ras proteins | nanoclusters/nanodomains | plasma membrane | molecular dynamics simulation

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Section: Resultsmentioning

confidence: 99%

Organization, dynamics, and segregation of Ras nanoclusters in membrane domains

Janosi

Hancock

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

165

241

View full text Add to dashboard Cite

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“…To cope with the multiple length-scale problem of complex protein systems, several multiscale-modeling methods have been proposed, which partition a complex system in different space regions with varying degree of chemical resolution defined in an ad hoc fashion prior to the simulation. They rely on the idea of coupling theoretical methods with different levels of coarsegraining, i.e., quantum, atomistic, mesoscopic, or continuumscale approaches, [23][24][25][26][27] within one simulation method. However, such techniques generally lack transferability, because they are specifically adapted to the nature of the physical problem under consideration and, thus, are not suitable for reproducing the multiscale relaxation dynamics of complex protein systems far from equilibrium.…”

Section: Introductionmentioning

confidence: 99%

A novel computer simulation method for simulating the multiscale transduction dynamics of signal proteins

Peter

Dick

Baeurle

2012

The Journal of Chemical Physics

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Signal proteins are able to adapt their response to a change in the environment, governing in this way a broad variety of important cellular processes in living systems. While conventional moleculardynamics (MD) techniques can be used to explore the early signaling pathway of these protein systems at atomistic resolution, the high computational costs limit their usefulness for the elucidation of the multiscale transduction dynamics of most signaling processes, occurring on experimental timescales. To cope with the problem, we present in this paper a novel multiscale-modeling method, based on a combination of the kinetic Monte-Carlo-and MD-technique, and demonstrate its suitability for investigating the signaling behavior of the photoswitch light-oxygen-voltage-2-Jα domain from Avena Sativa (AsLOV2-Jα) and an AsLOV2-Jα-regulated photoactivable Rac1-GTPase (PA-Rac1), recently employed to control the motility of cancer cells through light stimulus. More specifically, we show that their signaling pathways begin with a residual re-arrangement and subsequent H-bond formation of amino acids near to the flavin-mononucleotide chromophore, causing a coupling between β-strands and subsequent detachment of a peripheral α-helix from the AsLOV2-domain. In the case of the PA-Rac1 system we find that this latter process induces the release of the AsLOV2-inhibitor from the switchII-activation site of the GTPase, enabling signal activation through effector-protein binding. These applications demonstrate that our approach reliably reproduces the signaling pathways of complex signal proteins, ranging from nanoseconds up to seconds at affordable computational costs.

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“…More generally, the way the membrane solvates other components, such as membrane proteins, and even mediates their interactions with each other will be affected by these intrinsic properties. Specific consequences of this latter point are less well understood, but computational modeling methods suitable to examine such problems are emerging [34][35][36] .In one intriguing example, a recent computational study of the A 2A G protein-coupled receptor in membrane environments reveals a structural instability of helix II in cholesterolpoor membranes. Cholesterol interaction apparently stabilizes this helix and has been proposed as a possible explanation for the observation that the A 2A receptor couples to G protein only in the presence of cholesterol 37 .…”

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confidence: 99%

Molecular mechanisms in signal transduction at the membrane

Groves

Kuriyan

2010

Nat Struct Mol Biol

262

255

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Signal transduction originates at the membrane, where the clustering of signaling proteins is a key step in transmitting a message. Membranes are difficult to study, and their influence on signaling is still only understood at the most rudimentary level. Recent advances in the biophysics of membranes, surveyed in this review, have highlighted a variety of phenomena that are likely to influence signaling activity, such as local composition heterogeneities and long-range mechanical effects. We discuss recent mechanistic insights into three signaling systems-Ras activation, Ephrin signaling and the control of actin nucleation-where the active role of membrane components is now appreciated and for which experimentation on the membrane is required for further understanding.The influence of the membrane surface environment on the behavior of proteins that are localized to the vicinity of the membrane is still poorly understood. This contrasts starkly with our now quite sophisticated understanding of the structural and chemical aspects of the individual protein components 1 . This lack of knowledge is a natural consequence of the fact that membranes are difficult to study in vitro and that detailed quantitative information is difficult to obtain in vivo 2 . The relative inaccessibility of membranes to classical methods of study effectively cloaks their role in signaling biochemistry. We suggest that what is known about membranes in signal transduction is just a glimmer of a much larger story, with many key aspects of membrane function still hidden beneath the cloak.Cell signaling relies on modular domains that generate protein-protein interactions at the membrane 3,4 . Equally critical are domains that recognize specific phospholipids and are thereby responsive to changes in membrane composition 5 , as best exemplified by the family of protein kinase C (PKC) isozymes 6,7 . The PKC isozymes transduce signals arising from the hydrolysis of phospholipids in the membrane and have a protein kinase domain linked to C1 domains and a C2 domain (Fig. 1). The C1 domains bind to diacylglycerol (DAG), whereas the C2 domain binds to negatively charged lipids, such as phosphatidylinositol-4,5,-bisphosphate (PIP 2 ) and to Ca 2+ ions 6,7 . The activation of PKC involves priming by phosphorylation, followed by the recruitment of PKC to the membrane by PIP 2 , Ca 2+ and DAG 7,8 . One important principle that emerged from PKC studies is that the individual lipidbinding modules of PKC have insufficient affinity for their target lipids and so require that both PIP 2 and DAG be present for effective activation of the enzyme. This requirement for © 2010 Nature America, Inc. All rights reserved. Correspondence should be addressed to J.K. (kuriyan@berkeley.edu) or J.T.G. (Jtgroves@lbl.gov). COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Published as: Nat Struct Mol Biol. 2010 June ; 17(6): 659-665. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscriptmultiple targeting signals is ofte...

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Systematic multiscale simulation of membrane protein systems

Cited by 93 publications

References 50 publications

Organization, dynamics, and segregation of Ras nanoclusters in membrane domains

Organization, dynamics, and segregation of Ras nanoclusters in membrane domains

A novel computer simulation method for simulating the multiscale transduction dynamics of signal proteins

Molecular mechanisms in signal transduction at the membrane

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