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. Tong D, Voth GA. Microtubule Simulations Provided Insight into the Molecular Mechanism Underlying Dynamic Instability. Biophysical Journal.2020; 118(12) 2938-2951
  2. Bidone TC, Skeeters AV, Oakes PW, Voth GA. Multiscale Model of Integrin Adhesion Assembly. POLS Computational Biology. 2019; 15(6):e1007077

  3. Bidone TC, Polley A, Jin J, Driscoll T, Iwamoto D, Calderwood D, Schwartz MA, Voth GA. Coarse-Grained Simulation of Full-Length Integrin Activation. Biophysical Journal. 2019; 116(6) 1000-1010

  4. Freedman SL, Suarez C, Winkelman JD, Kovar DR, Voth GA, Dinner AR, Hocky GM. Mechanical and Kinetic Factors Drive Sorting of F-actin Crosslinkers on Bundles. Proceedings of the National Academy of Sciences. 2019; 116(13) 16192-16197

  5. Harker AJ, Katkar HH, Bidone TC, Aydin F, Voth GA, Applewhite DA, Kovar DR. Ena/VASP Processive Elongation is Modulated by Avidity on Actin Filaments Bundled by the Filopodia Crosslinker Fascin. Molecular Biology of the Cell. 2019; 30(7) 851-862SV

  6. Schramm AC, Hocky GM, Voth GA, Martiel J-L, De La Cruz EM. Plastic Deformation and Fragmentation of Strained Actin Filaments. Biophysical Journal. 2019; 117(3) 453-463

 Researchers: Fikret Aydin, Tamara Bidone, Harsh KatkarSriramvignesh Mani


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. Yu A, Skorupka K, Pak AJ, Ganser-Pornillos BK, Pornillos O, Voth GA, TRIM5α Self-Assembly and Compartmentalization of the HIV-1 Viral Capsid. Nature Comm. 2020; 11:1-10.

  2. 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.

  3. Pak AJ, Dannenhoffer-Lafage T, Voth GA. Systematic Coarse-Grained Lipid Force Fields with Semiexplicit Solvation via Virtual Sites. J Chem Theory Comput. 2019; 15(3):2087–2100.

  4. Pak AJ, Voth GA. Advances In Coarse-Grained Modeling of Bio-Macromolecular Complexes. Current Opinion in Structural Biology. 2018 ;52:119-126

  5. Madsen JJ, Grime JMA, Rossman JS, Voth GA. Entropic forces drive clustering and spatial localization of influenza A M2 during viral budding. PNAS. 2018 ;115(37).


Researchers: Alvin Yu, Alex Pak, Alek Durumeric


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

  2. 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

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

  4. 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.

  5. 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.

  6. Madsen JJ, Sinitskiy AV, Li J, Voth GA. Highly Coarse-grained Representations of Transmembrane Proteins. J. Chem. Theory Comput. 2017

  7. Davtyan A, Simunovic M, Voth GA. The Mesoscopic Membrane with Proteins Model (MesM-P). J. Chem. Phys. 2017; 147.


Researchers: Zack Jarin, Mijo SimunovicJesper MadseAram Davtyan