The University of Chicago

Simulations of Biomolecular Systems

Multiscale Modeling of the 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. S. Mani, H. H. Katkar, and G. A. Voth, “Compressive and Tensile Deformations Alter ATP Hydrolysis and Phosphate Release Rates in Actin Filaments”, J. Chem. Theory Comp. 17, 1900-1913 (2021).

  2. K. E. Homa, V. Zsolnay, C. A. Anderson, M. E. O’Connell, E. M. Neidt, G. A. Voth, T. C. Bidone,* and D. R. Kovar,* “Formin Cdc12’s Specific Actin Assembly Properties are Tailored for Cytokinesis in Fission Yeast”, Biophys. J. 120, 2984–2997 (2021). (*Co-corresponding authors) PMCID: In progress

  3. G. M. Hocky, C. V. Sindelar, W. Cao, G. A. Voth, and E. M. De La Cruz, “Structural Asymmetry in Fast- And Slow-Severing Actin-Cofilactin Boundaries”, J. Biol. Chem. 296, 100337(1-9) (2021).PMCID: PMC7961102

  4. V. Zsolnay, H. H. Katkar, S. Z. Chou, T. D. Pollard, and G. A. Voth, “Structural Basis for Polarized Elongation of Actin Filaments”, Proc. Nat. Acad. Sci. USA 117, 30458–30464 (2020). PMCID: PMC7720195

  5. Tong D, Voth GA. Microtubule Simulations Provided Insight into the Molecular Mechanism Underlying Dynamic Instability. Biophysical Journal.2020; 118(12) 2938-2951

  6. Bidone TC, Skeeters AV, Oakes PW, Voth GA. Multiscale Model of Integrin Adhesion Assembly. POLS Computational Biology. 2019; 15(6):e1007077

Researchers: Sriramvignesh Mani, Vilmos Zsolnay

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. V. Monje-Galvan and G. A. Voth, “Molecular Interactions of the M and E Integral Membrane Proteins of SARS-CoV-2”, Faraday Discussions (in press). PMCID: PMC8095202 

  2. A. Tan,# A. J. Pak,# D. R. Morado, G. A. Voth,* and J. A. G. Briggs,* “Immature HIV-1 Assembles From Gag Dimers Leaving Partial Hexamers at Lattice Edges as Substrates for Proteolytic Maturation”, Proc. Nat. Acad. Sci. USA 118, e2020054118 (2021). (#Authors contributed equally, *Corresponding authors) PMCID: PMC7826355

  3. A. Yu, K. Skorupka, A. J. Pak, B. K. Ganser-Pornillos, O. Pornillos, and G. A. Voth, “TRIM5α Self-Assembly and Compartmentalization of the HIV-1 Viral Capsid”, Nature Comm. 11, 1307(1-10) (2020). PMCID: PMC7066149

  4. A. Yu, E. M.Y. Lee, J. Jin, and Gregory A. Voth, “Atomic-scale Characterization of Mature HIV-1 Capsid Stabilization by Inositol Hexakisphosphate (IP6)”, Science Advances 6, eabc645 (2020). PMCID: PMC74944349

  5. V. Monje-Galvan­ and G. A. Voth, “Binding Mechanism of the Matrix Domain of HIV-1 Gag to Lipid Membranes”, eLife 9, e58621 (2020). PMCID: PMC7476761

  6. Pak AJ, Grime JMA, Yu A, Voth GA. Off-Pathway Assembly: A Broad-Spectrum Mechanism of Action for Drugs That Undermine Controlled HIV-1 Viral Capsid Formation. J. Am. Chem. Soc. 2019; 141(26):10214-10224.

  7. Researchers: Alvin Yu, Arpa Hudait, Mandira Dutta, Puja Banerjee

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 a 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. Z.  Jarin, A. J. Pak, P. Bassereau, and G. A. Voth, “Lipid-Composition-Mediated Forces Can Stabilize Tubular Assemblies of I-BAR Proteins”, Biophys. J. 120, 46–54 (2021). PMCID: PMC7820731

  2. Jarin Z, Pak AJ, Bassereau P, Voth GA. Membrane-Mediated Forces Can Stabilize Tubular Assemblies of I-BAR Proteins. Biophys. J. Submitted

  3. Jarin Z, Tsai F-C, Davtyan A, Pak AJ, Bassereau P, Voth GA. Unusual Organization of I-BAR Proteins on Tubular and Vesicular Membranes. Biophys. J. 2019; 117(3):553-562

  4. T. G. Flower, Y. Takahashi, A. Hudait, K. Rose, N. Tjahjono, A. J. Pak, A. L. Yokom, X. Liang, H.-G. Wang, F. Bouamr, G. A. Voth, and J. H. Hurley, “A Helical Assembly of Human ESCRT-I Scaffolds Reverse-Topology Membrane Scission”, Nat. Struct. Mol. Biol. 27, 570–580 (2020). PMCID: PMC7339825

  5. Simunovic M, Bassereau P, Voth GA. Organizing Membrane-Curving Proteins: The Emerging Dynamical Picture. Curr. Opin. Struct. Biol. 2018; 51:99-105

  6. Prévost C, Cohen ME, Kory N, Lin Q, Voth GA, Farese, Jr. RV, Walther TC. Mechanism of Targeting of Amphipathic Helix-Containing Proteins to Lipid Droplets. Dev. Cell. 2018; 44(1):73-86.

  7. Simunovic M, Manneville J-B, Renard H-F, Evergren E, Raghunathan K, Kenworthy AK, Voth GA, Prost J, McMahon HT, Johannes L, et al. Friction Mediates Scission of Tubular Membranes Scaffolded by BAR Proteins. Cell. 2017; 170.

Researchers: Zack Jarin, Arpa Hudait