NSF-ANR: Cellular Crowding and Condensation Under Shear Flow

Michigan State University, East Lansing MI

Investigators

Abstract

Inside biological cells there is a highly concentrated mix of biomolecules, proteins and nucleic acids, that interact frequently. Most of these interactions are non-specific, but they may nevertheless lead to clustering, aggregation, and the formation of phase separated regions, all of which can have a significant impact on biological function. In this project, hydrodynamic flow present inside living cells is studied as a new dimension that is expected to modulate transient molecular interactions and enhance or suppress aggregation and phase separation as a consequence. The outcome of these efforts is a more complete, fully dynamic view of how biomolecules interact in dense biological environments. The project involves a close integration between biophysical experiments and computer simulations. There are synergistic benefits from international collaboration between US and French groups to develop complementary computational expertise for large-scale simulations of interacting biomolecules in the presence of external flow. The impact of the research activities is enhanced by extensive involvement of undergraduate and graduate students in highly interdisciplinary research with a strong focus on the continued recruitment and support of females and underrepresented minorities in biophysical research. The development of a new physics curriculum targeted at life science majors is another goal for making physics education more relevant for biology topics. In another direction, a public outreach component is developed where physical demonstrations are combined with computer simulations to illustrate the abstract concept of diffusion via particle interactions in the context of biology. In dense cellular environments biomolecules interact frequently via transient non-specific interactions. Such interactions may lead to clustering, condensation, and aggregation. Here the effect of shear flow on such processes is examined as a new dimension towards understanding the behavior of biomolecules in realistic biological environments. Shear flow is present in biological cells and is expected to modulate transient interactions and condensation and potentially facilitate aggregation. Different model systems will be investigated via experiments and computer simulations. The model systems include concentrated solutions of globular proteins to study non-condensing transient clustering, peptide-RNA mixtures to study condensation, and highly dynamic intrinsically disordered peptides to examine intra- and intermolecular diffusion in crowded and condensing environments. Experiments involve nano-scale spectroscopy and micron-scale microscopy techniques; computer simulations emphasize a highly multi-scale approach in order to bridge between molecular and cellular scales. International collaboration between US and French groups adds complementary expertise for simulating large-scale biomolecular systems in the presence of hydrodynamic flow. The impact of the research activities is enhanced by extensive involvement of undergraduate and graduate students in highly interdisciplinary research with a strong focus on the continued recruitment and support of females and underrepresented minorities in biophysical research. The development of a new physics curriculum targeted at life science majors is another goal for making physics education more relevant for biology topics. In another direction, a public outreach component is developed where physical demonstrations are combined with computer simulations to illustrate the abstract concept of diffusion via particle interactions in the context of biology. This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigator and ANR funds the partners in France. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.