Multiscale simulations of protein-facilitated membrane remodeling
Introduction
Biological membranes are multicomponent, self-assembled molecular sheets that surround the cells and its organelles. Besides separating the cell from the environment, compartmentalizing its components, and providing a mechanical protection, membranes play a crucial role in many biological processes that are vital for cell’s survival and function. Examples of such processes are cell adhesion, cell signaling, and the selective transport of ions and organic molecules in and out of the cell (Conner and Schmid, 2003, McMahon and Gallop, 2005). In order to perform such a diverse set of functions, membranes possess inherently multiscale material properties. While exhibiting fluid properties at molecular scales, membranes behave like elastic sheets at length scales that are large compared to their thickness (Helfrich, 1973). As a result, membranes can exhibit a remarkable variety of shapes and morphologies (Lipowsky, 1991) dictated by their composition and the surrounding environment (Johannes et al., 2014, Lipowsky and Sackmann, 1995).
Membrane remodeling is facilitated by the action of proteins that bind peripherally to the membrane, partially insert their domains, or are fully included into the bilayer (McMahon and Gallop, 2005). These proteins induce a local asymmetry between the layers of the membrane, which generates spontaneous curvature. It is believed that a cooperative behavior of multiple proteins gives rise to large-scale membrane remodeling (Gallop et al., 2006, Jao et al., 2010, Saarikangas et al., 2009, Zimmerberg and Kozlov, 2006). Perhaps the most studied membrane remodelers are Bin/Amphiphysin/Rvs (BAR) domain proteins. They play a crucial role in many cellular processes, including clathrin-mediated and clathrin-independent endocytosis (Boucrot et al., 2015, Doherty and McMahon, 2009, Renard et al., 2015, Slepnev and De Camilli, 2000), T-tubule morphogenesis (Lee et al., 2002, Peachey and Eisenberg, 1978), cytokinesis (Arasada and Pollard, 2015), and many others. BAR domain is a crescent-shaped dimer with positively charged residues on its membrane-interacting surface (Frost et al., 2007, Gallop and McMahon, 2005). It is believed to generate curvature by a combination of (1) adhesive interactions with the membrane surface, (2) insertion of amphipathic helices, and (3) by forming three-dimensional ordered structures that mold membrane tubules (Simunovic et al., 2015).
The inherently multiscale nature of membrane remodeling makes it quite challenging to study the mechanisms behind these phenomena. Due to a strong coupling between microscopic properties of the membrane (e.g., diffusion rate and packing defects) and its macroscopic characteristics (e.g., bending modulus and bulk compressibility), membrane remodeling cannot be studied using a single computational technique; rather, it requires a hierarchical approach. Atomistic simulations can provide invaluable insights into direct protein-membrane interactions, see, e.g., (Blood and Voth, 2006, Blood et al., 2008, Cui et al., 2009, Lyman et al., 2010). However, the high computational cost limits their applicability beyond single protein simulations. Coarse-grained (CG) simulations, on the other hand, can reach biologically relevant time and length scales, owing to a reduction in the number of degrees of freedom achieved by grouping lipid and protein atoms into CG sites and, often, by an implicit treatment of the bulk solvent. The effective interactions between CG sites can be derived, at least mostly, from atomistic simulations (the so-called bottom-up approach) (Ayton and Voth, 2009b, Ayton et al., 2010, Izvekov and Voth, 2009, Srivastava and Voth, 2012, Srivastava and Voth, 2014). The resulting CG models can be very valuable for studying complex behavior of protein cooperation during membrane remodeling.
In recent years, a number of mesoscopic membrane models have also been developed. Those models are beyond the resolution of individual molecules, but rather employ quasi-particle description of the membrane, often complimented with the use of vector as well as other continuum or semi-continuum fields that can represent the inhomogeneity of membrane composition or protein concentration on the membrane (Ayton et al., 2007, Ayton et al., 2009, Shiba and Noguchi, 2011, Sreeja et al., 2015).
This Review will survey the multiscale computational methods developed in our group for studying membrane-protein interactions and membrane remodeling (Ayton and Voth, 2009a, Ayton and Voth, 2010b). The remainder of this article is organized as follows: Section 2 shortly presents different CG models of lipids and proteins and discusses the main results of the CG approach. Section 3 is dedicated to mesoscopic modeling. We present the Elastic Membrane Version 2 (EM2) model and recapitulate the key results that this model predicts. We also draw a brief comparison with mesoscopic models that have been developed by other groups. Section 4 contains the concluding remarks.
Section snippets
CG simulations of membrane remodeling by BAR proteins
Large-scale atomistic simulations have provided valuable insights into mechanisms of protein-membrane interactions and curvature coupling, especially by BAR proteins such as endophilin (Blood and Voth, 2006, Blood et al., 2008, Cui et al., 2009, Lyman et al., 2010). However, at present it is too challenging to expand those simulations to treat many proteins bound to the membrane. To reach the sub-cellular length and time scales (∼μm and ∼ms, respectively) that can be examined experimentally,
Mesoscopic simulations of protein-induced membrane remodeling
The global membrane remodeling is a very slow process that occurs on the order of microseconds to even seconds. The CG simulations make it possible to study the early stages of membrane remodeling. While the CG models described before can simulate systems containing millions of lipids, simulating cellular-scale vesicles at microsecond or longer time scales is still too challenging for CG MD. A mesoscopic approach that operates beyond the resolution of individual molecules can model the dynamics
Conclusions and perspectives for the future
In this Review, we focused on CG and mesoscopic approaches developed in our group that allowed us to study membrane remodeling by proteins at high resolution, but also at long length and time scales. To successfully model a complex cellular process such as membrane remodeling, in which the molecular and the macroscopic levels are innately connected, a careful consideration of all the scales is needed.
For the future, advances in modeling large biological systems will require us to derive a
Acknowledgments
This work was supported by a grant from the National Institutes of Health (R01-GM063796).
References (75)
- et al.
Systematic multiscale simulation of membrane protein systems
Curr. Opin. Struct. Biol.
(2009) - et al.
Multiscale computer simulation of the immature HIV-1 virion
Biophys. J.
(2010) - et al.
Multiscale simulation of protein mediated membrane remodeling
Semin. Cell Dev. Biol.
(2010) - et al.
Membrane remodeling from N-BAR domain interactions: insights from multi-scale simulation
Biophys. J.
(2007) - et al.
Coupling field theory with continuum mechanics: a simulation of domain formation in giant unilamellar vesicles
Biophys. J.
(2005) - et al.
New insights into BAR domain-induced membrane remodeling
Biophys. J.
(2009) - et al.
Factors influencing local membrane curvature induction by N-BAR domains as revealed by molecular dynamics simulations
Biophys. J.
(2008) The minimum energy of bending as a possible explanation of the biconcave shape of the human red blood cell
J. Theor. Biol.
(1970)- et al.
Coarse-grained modeling of the actin filament derived from atomistic-scale simulations
Biophys. J.
(2006) - et al.
Membrane binding by the endophilin N-BAR domain
Biophys. J.
(2009)
Understanding the role of amphipathic helices in N-BAR domain driven membrane remodeling
Biophys. J.
A new material concept for the red cell membrane
Biophys. J.
F-BAR proteins join the BAR family fold
Structure
On the role of anisotropy of membrane constituents in formation of a membrane neck during budding of a multicomponent membrane
J. Biomech.
Roles of amphipathic helices and the bin/amphiphysin/rvs (BAR) domain of endophilin in membrane curvature generation
J. Biol. Chem.
Systematic multiscale parameterization of heterogeneous elastic network models of proteins
Biophys. J.
Water under the BAR
Biophys. J.
Lateral pressure profile, spontaneous curvature frustration, and the incorporation and conformation of proteins in membranes
Biophys. J.
Oligomerization but not membrane bending underlies the function of certain F-BAR proteins in cell motility and cytokinesis
Dev. Cell
Coupling field theory with mesoscopic dynamical simulations of multicomponent lipid bilayers
Biophys. J.
Helicoids in the T system and striations of frog skeletal muscle fibers seen by high voltage electron microscopy
Biophys. J.
Membrane-mediated aggregation of curvature-inducing nematogens and membrane tubulation
Biophys. J.
Effect of chain length and unsaturation on elasticity of lipid bilayers
Biophys. J.
Molecular mechanisms of membrane deformation by I-BAR domain proteins
Curr. Biol.
When physics takes over: BAR proteins and membrane curvature
Trends Cell Biol.
Protein-mediated transformation of lipid vesicles into tubular networks
Biophys. J.
F-BAR/EFC domain proteins: some assembly required
Dev. Cell
Structure and interactions of fully hydrated dioleoylphosphatidylcholine bilayers
Biophys. J.
A systematic methodology for defining coarse-grained sites in large biomolecules
Biophys. J.
A role for F-BAR protein Rga7p during cytokinesis in S. pombe
J. Cell. Sci.
Hybrid coarse-graining approach for lipid bilayers at large length and time scales
J. Phys. Chem. B
A second generation mesoscopic lipid bilayer model: connections to field-theory descriptions of membranes and nonlocal hydrodynamics
J. Chem. Phys.
Hierarchical coarse-graining strategy for protein-membrane systems to access mesoscopic scales
Faraday Discuss.
Direct observation of Bin/amphiphysin/Rvs (BAR) domain-induced membrane curvature by means of molecular dynamics simulations
Proc. Natl. Acad. Sci. USA
Endophilin marks and controls a clathrin-independent endocytic pathway
Nature
Regulated portals of entry into the cell
Nature
Amphipathic DNA origami nanoparticles to scaffold and deform lipid membrane vesicles
Angew. Chem.
Cited by (13)
Physical principles of cellular membrane shapes
2022, Plasma Membrane ShapingOn the role of curved membrane nanodomains, and passive and active skeleton forces in the determination of cell shape and membrane budding
2021, International Journal of Molecular SciencesSPICA Force Field for Proteins and Peptides
2021, Journal of Chemical Theory and ComputationLarge-Scale Molecular Dynamics Simulations of Cellular Compartments
2021, Methods in Molecular BiologyAtomistic Simulations of Membrane Ion Channel Conduction, Gating, and Modulation
2019, Chemical Reviews