Simulations of Biomolecular Systems


Multiscale Modeling of the Actin Cytoskeleton

The actin cytoskeleton is central to the life cycle of a cell, giving it structure as well as powering cell motion and cell division. Crucial to this activity is the ability to regulate the nucleation, growth and disassembly of actin filaments with precise spatiotemporal resolution. Cells accomplish this level of control by using a diverse array of proteins that bind to actin monomers and to polymerized actin filaments, as well as using the hydrolysis of a bound ATP molecule as an internal clock. Important behavior in the cytoskeleton spans times from picoseconds (ATP hydrolysis) to many minutes (cellular migration), and actin polymers can be many micrometers in length while having their mechanical properties dictated by protein-protein interactions at the sub-nanometer scale. Simulations and modeling can be crucial to understanding the complex behaviors that can occur in the cytoskeleton and for interpreting the results of biochemical and biophysical experiments. In the Voth group, we use a combination of molecular simulations, coarse grained simulations, enhanced sampling techniques, and statistical physics models, in direct collaboration with experimental leaders in the field.

Relevant Papers:

  1. Christensen JR, Hocky GM, Morganthaler AN, Homa KE, Hitchcock-DeGregori SE, Voth GA, Kovar DR. Competition Between Tropomyosin, Fimbrin, and ADF/Cofilin Drive Their Sorting to Distinct Actin Filament Networks. eLife. Submitted

  2. Zimmerman D, Homa KE, Hocky GM, Pollard LW, De La Cruz EM, Voth GA, Trybus KM, Kovar DR. Mechanosensitive Inhibition of Formin Facilitates Contractile Actomyosin Ring Assembly. Submitted

  3. Winkelman JD, Suarez C, Hocky GM, Harker AJ, Christensen JR, Morganthaler AN, Voth GA, Bartles JR, Kovar DR. Fascin and α-Actinin-bundled Networks Contain Intrinsic Structural Features That Drive Protein Sorting. Current Biology. 2016 ;26(20):2697–2706.PubMedDOIBibTex

  4. Li Y, Christensen JR, Homa KE, Hocky GM, Fok A, Sees JA, Voth GA, Kovar DR. The F-Actin Bundler α-Actinin Ain1 is Tailored for Ring Assembly and Constriction during Cytokinesis in Fission Yeast. Mol Biol Cell. 2016 ;27(11):1821-1833.DOIBibTex

  5. Hocky GM, Baker JL, Bradley MJ, Sinitskiy AV, De La Cruz EM, Voth GA. Cations Stiffen Actin Filaments by Adhering a Key Structural Element to Adjacent Subunits. J. Phys. Chem. B. 2016 ;120(20).DOIBibTex

  6. Baker JL, Courtemanche DL, Parton DL, McCullagh M, Pollard TD, Voth GA. Electrostatic Interactions Between the Bni1p Formin FH2 Domain and Actin Influence Actin Filament Nucleation. Structure. 2015 ;23.DOIBibTex

  7. McCullagh M, Saunders MG, Voth GA. Unraveling the Mystery of ATP Hydrolysis in Actin Filaments. J. Am. Chem. Soc. . 2014 ;136(37):13053–13058.DOIBibTex

 Researchers: Fikret Aydin, Tamara Bidone, Aram Davtyan, Glen Hocky, Harsh Katkar, Rui Sun


Viral Capsid Assembly and Infection Pathway

The Voth group is interested in applying computational methods to understand the self-assembly and dynamics of macromolecular assemblies, including the HIV-1 viral capsid, These systems are difficult to simulate in part because traditional molecular dynamics provides insufficient sampling of high-energy states over the timescales accessible with current computational power. The large size, complex composition, and slow dynamics of these systems require the use of more advanced simulation techniques. The main paradigm the Voth Group uses to overcome this limitation is coarse-grained methods.


Relevant Papers:

  1. Grime, J.M.A; Dama, J.F.; Ganser-Pornillos, B.K.; Woodward, C.L.; Jensen, G.J.; Yeager, M.J.; Voth, G.A. (2016). Coarse-grained simulation reveals key features of HIV-1 Capsid Self-Assembly. Nat. Comm. 7 (1156): 1-11

  2. Saunders, M.G. & Voth, G. A. (2012). Coarse-graining methods for computational biology. Ann. Rev. Biophys. in press

  3. Grime, J. & Voth, G. A. (2012). Early stages of the HIV-1 capsid protein lattice formation. Biophys. J. in press.

  4. Ayton, G. S. & Voth, G. A. (2010). Multiscale computer simulation of the immature HIV-1 virion. Biophys. J. 99, 2757-65.

  5. Zhang, Z. & Voth, G. A. (2010). Coarse-Grained Representations of Large Biomolecular Complexes from Low-Resolution Structural Data. J. Chem. Theor. Comp. 6, 2990-3002.

  6. Saunders M. G. and G. A. Voth (2012). "Coarse-graining of multiprotein assemblies." Current Opinion in Structural Biology.

 7. Zhang, Z. Y., K. Y. Sanbonmatsu, et al. (2011). "Key Intermolecular Interactions in the E. coli 70S Ribosome Revealed by Coarse-Grained Analysis." Journal of the American Chemical Society 133(42): 16828-16838.

Researchers: John Grime, Alex Pak, Alek Durumeric, Laura Tociu


Multiscale Study of Membrane-Remodeling by Proteins


Remodeling of biological membranes induced by proteins is an essential physiological process that facilitates key cellular tasks such as endocytosis, pathogen infection, immune response, cellular motility, protein trafficking, etc. By using advanced multiscale methods developed in our group, we combine all-atom, coarse-grained, and continuum mechanics simulations in a powerful way to elucidate the molecular nature of membrane processes, as well as their large-scale physical and biophysical properties. Specifically, we focus on multiscale study of membrane remodeling induced by Bin/Amphiphysin/Rvs-homology (BAR) superfamily of proteins and their connection to cellular mechanisms.

BAR proteins are essential modulators of the dynamics of cellular membranes. Given our recent advancements in developing multiscale techniques, we are in a unique position to understand the structural, biological, and physical properties of these processes at both the molecular and mesoscopic levels. Specifically, we study the molecular mechanism of BAR-mediated remodeling and how the molecular interactions couple with the long-wavelength behavior of biological membranes. Recently, our achievement in reconstructing molecular configurations from remodeled continuum membranes has allowed us to study the molecular details of very large remodeled vesicles (visible with optical microscopy!), which had not yet been studied theoretically.

Relevant Papers:

  1. Simunovic, M.; Evergren, E.; Golushko, I.; Prévost, C.; Renard, H.-F.; Johannes, L.; McMahon, H. T.; Lorman, V.; Voth, G. A.; Bassereau, P. How Curvature-Generating Proteins Build Scaffolds on Membrane Nanotubes. Proc. Natl. Acad. Sci. 2016, 113, 11226–11231.

  2. Simunovic, M.; Voth, G. A. Membrane Tension Controls the Assembly of Curvature-Generating Proteins. Nat Commun 2015, 6, 7219.

  3. Simunovic, M.; Voth, G. A.; Callan-Jones, A.; Bassereau, P. When Physics Takes Over: BAR Proteins and Membrane Curvature. Trends in Cell Biology, 2015, 25, 780–792.

  4. Mim, C.; Cui, H.; Gawronski-Salerno, J. a; Frost, A.; Lyman, E.; Voth, G. A.; Unger, V. M. Structural Basis of Membrane Bending by the N-BAR Protein Endophilin. Cell 2012, 149, 137–145.

  5. Cui, H.; Lyman, E.; Voth, G. A. Mechanism of Membrane Curvature Sensing by Amphipathic Helix Containing Proteins. Biophys. J. 2011, 100, 1271–1279.

  6. Blood, P. D.; Voth, G. A. Direct Observation of Bin/amphiphysin/Rvs (BAR) Domain-Induced Membrane Curvature by Means of Molecular Dynamics Simulations. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 15068–15072.

Researchers: Zack Jarin, Jesper Madsen, Morris Cohen, Aram Davtyan