Allostery of Actin Filaments: Atomistic Simulations and Coarse-Grained Modeling

ChEMS Seminar

Featuring:
Dr. Jhih-Wei Chu,
Center for Biophysical Modeling and Simulation &
Department of Chemistry,
University of Utah

Location: Computer Science (CS) 174

Abstract:
Actin filaments (F-actin) are the major component of the cytoskeleton and play a key role in many critical cellular processes such as cell locomotion, mitosis, meiosis, and cytokinesis. An actin filament is a polymer assembled from the protein actin (G-actin) via non-covalent interactions. In order for the cell to function properly at different stages of its life cycle, ATP hydrolysis and many other regulatory processes control the mechanical properties and polymerization of F-actin.

A molecular level understanding of the biological regulation of actin filaments is thus critical to many areas in biomedical engineering, biophysics, and cell biology.

After polymerizing into F-actin, the bound ATP in G-actin is hydrolyzed into ADP. Experimental studies suggested that ATP hydrolysis may induce conformational changes in the DNase I binding loop (DB-loop) of G-actin and in turn affects the properties of F-actin. Indeed, recent X-ray structures of monomeric actin in the ADP state and in the ATP state demonstrate that the DB-loop of G-actin does not have a well-defined secondary structure in the ATP state but folds into an Ą helix in the ADP state. In order to determine whether such a conformational change in the DB-loop is relevant to the regulation of F-actin, the structural and mechanical properties of monomeric actin, the trimer nucleus, and actin filaments are examined as a function of the conformation of the DB-loop using all-atom molecular dynamics (MD) simulations and coarse-grained (CG) modeling.

MD simulations and CG modeling indicate that the helical conformation of the DB-loop significantly weakens the inter-monomer interactions of actin assemblies, and thus leads to a wider, shorter and more disordered filament. The computed elastic properties of ATP bound and ADP bound filaments also agree well with available experimental data. Therefore, our results indicate that the changes in structural and mechanical properties of actin filaments after ATP hydrolysis can be attributed to a loop-to-helix transition of the DB-loop. By using molecular modeling and multiscale analysis, a direct connection is thus established between the alternate conformational states of G-actin and the properties of a filament. Finally, I will also present the principles of multiscale modeling and coarse-grained procedures that were adopted in this study.

About the Speaker:
Jhih-Wei Chu received his Ph.D. in Chemical Engineering from the Massachusetts Institute of Technology in 2004.  He is currently a Postdoctoral Research Associate at the Center for Biophysical Modeling and Simulation and the Department of Chemistry at the University of Utah.  His current research project focuses on Multiscale Modeling and Simulation of Actin Filaments.