Garegin Papoian of the University of North Carolina Chapel Hill is supported by a CAREER award from the Theoretical and Computational Chemistry program to carry out research on the development of a physico-chemical modeling technique for filipodia initiation and dynamics. The physical chemistry of these mesoscopic organelles is not well understood. In this research, Papoian and his group are elucidating the mechanism of the temporally-controlled self-assembly of actin-filament bundles that is driven by coupling among spatially-localized mechanical and chemical interactions. Models of filopodia growth-retraction dynamics are being developed which take into account the spatial localization of regulatory proteins.

The work is having a broad impact through its connection to basic biological science, but also through several outreach initiatives to high school students and under-represented minorities that Papoian is developing. He is also developing an online CyberBacteria project which will allow young students to experience the excitement of cutting-edge research problems.

Project Report

Cellular Cytoskeleton: Cells of higher organisms contain a network of semiflexible filaments, comprised of various proteins, with actin molecules playing a dominant role. This network, called cellular cytoskeleton, endows the cells with their shape and mechanical properties, and also is a key nexus for many cellular signaling pathways. Furthermore, actin polymerization processes and the activities of various associated motor proteins generate directional forces that are used both inside the cell to move around various vesicles or organelles, and also to interact with the external environment, leading to such critical cellular behaviors as cell motility and mechanosensation. Dynamically remodeling actin networks, which comprise the cellular cytoskeletons, are complex mechano-chemical systems, being far-out-of-equilibrium. In particular, non-linear processes in mechanics, chemistry and transport mutually couple to give rise to rich phenomenology of various resulting structures, from filament bundles to asters and three-dimensional filament meshes. Despite significant progress in understanding dynamics and regulation of actin networks, a comprehensive microscopic picture is still out of reach. Filopodia: Significant research efforts have been recently utilized to shed light on one of the important cellular structures, filopodia, which are long, finger-like cytoplasmic projections, based on parallel, bundled actin filaments. These structures are exquisitely regulated, extending from the leading edge of a migrating cell to explore the environment. Commonly, after initiation, filopodia grow and retract, exhibiting rich dynamical behaviors. Considerable experimental work on filopodia in the last decade has pointed to their essential role in regulating embryonic development, neural axon growth and other important biological processes. Dr. Papoian's laboratory has developed state-of-art computational models for investigating the self-assembly mechanisms and growth-retraction dynamics of filopodia. Their computational model of a filopodium provided a fully stochastic treatment of actin monomer diffusion and polymerization for each actin filament under stress of a fluctuating membrane. Importantly, they derived an analytical formula for the length of a filopodium at the steady-state, providing novel insights into the general problem of length-regulation in biology. Their formula suggested, for example, that filopodia may greatly elongate upon the diminution of force-generating motor activity inside the cell’s body. Computer simulations, carried out by the Papoian laboratory, shed light on a number of important experimental observations. For example, filopodial protrusions are highly dynamic, demonstrating ubiquitous growth-retraction cycles, where their origin was unclear. Using computational approaches and mean-field analyses, they proposed a molecular mechanism explaining this phenomenon. Papoian group discovered that molecular fluctuations, caused by the binding of capping proteins, become amplified, inducing a macroscopic instability in the filopodial dynamics. Their model also explained why filopodia may have a short lifetime. The Papoian laboratory also investigated whether the active transport of G-actins to the filopodial tip may elongate the filopodium. When considering biological active transport by molecular motors, the biology textbooks envision a conveyor-like delivery of materials to the "construction site." However, the Papoian group showed that the literal implementation of this idea in a kinetic scheme results in highly inefficient transport. They found that a motor transport system should contain cooperativity to prevent the sequestration of cargo and alleviate traffic jams. Their simulations and analytical theory explained how the filopodial length can be differentially regulated via diffusional and active transports. Outreach: Dr. Papoian served as an Organizing Committee member for the 44th International Chemistry Olympiad hosted by the United States (www.icho2012.org). 75 countries participated in the Olympiad, sending 280 high school students, who were the winners of the corresponding national olympiads. He composed two preparatory problems and contributed one of the eight problems on the Final Exam, and participated in grading the exams. Dr. Papoian’s group members participated in many outreach activities over the course of the award duration, including contributing to a stand with DNA origami at the Biomolecular Discovery Dome at this Spring’s Maryland Day, attended by many young children. This effort was nationally highlighted by the Biophysical Society. Dr. Papoian served on the Research Day Judging Committee at Howard University. "Virtual Substance": Numerical experiments, based on molecular simulations and visualization, provide an appealing platform for engaging students in active learning of physical chemistry. Such an educational project, has been used as the main platform for teaching students in physical chemistry labs at UNC Chapel Hill and at Erskine College. As part of educational activities supported by CHE-715225, Dr. Papoian’s group made important contributions to the "Virtual Substance" project. Previously, only single atom types could be simulated using the "Virtual Substance" software, precluding the study of molecules composed of different atoms and molecular mixtures. Dr. Papoian's group has addressed this problem, significantly broadening "Virtual Substance" capabilities, making it possible to simulate arbitrary heteropolymers and molecular mixtures and developing a unit on micelle formation, where students can learn about the interplay between the entropy and energy.

Agency
National Science Foundation (NSF)
Institute
Division of Chemistry (CHE)
Application #
1119958
Program Officer
Evelyn M. Goldfield
Project Start
Project End
Budget Start
2010-12-01
Budget End
2014-04-30
Support Year
Fiscal Year
2011
Total Cost
$438,493
Indirect Cost
Name
University of Maryland College Park
Department
Type
DUNS #
City
College Park
State
MD
Country
United States
Zip Code
20742