Physical and computational modeling of biomolecular crowding, confinement, organization, and interactions

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This proposal is aimed at understanding biomolecular phenomena occurring in a crowded medium or near cell membranes. It consists of four objectives as outlined below. Because of its significance in interpreting chromosome experiments, there has been renewed interest in studying a chromosome-like (heterogeneous) polymer in a confined and crowded space. Using computer simulations, we will investigate how molecular crowding, confinement, chain cross-linking and chain heterogeneity influence the spatial organization of such a polymer. This effort will help identify the key parameters for controlling chromosome organization, especially in bacterial cells, and advance the field of chromosome biophysics by offering biophysical models for interpreting experiments. Antimicrobial peptides (AMPs) are naturally occurring peptide antibiotics. They attach to and rupture bacterial membranes. There has been much interest in utilizing them as new antibiotics. A barrier to this effort is peptide's interactions with the host cells, which diminish the number of peptides that attack bacteria. Using a biophysical model, we plan on characterising the peptide parameters for enhanced antimicrobial activity in a biologically relevant medium (i.e., a mixture of host cells and bacteria). We will also study how bacterial populations respond to AMPs. For this, we will build up on our earlier reaction model and employ a stochastic simulation approach to the reaction, by which AMPs kill bacteria. The outcome of this project will likely show how to overcome the barrier, help us understand better how AMPs work and thus benefit our endeavor in finding potent AMPs. Another determinant of AMP activity is the outer membranes (OMs) enclosing Gram-negative bacteria. Lipopolysaccharide (LPS) is a key component of the outer layer of the OM, whereas phospholipids are mainly localized to the inner layer. By extending the biophysical models we developed, we will investigate how AMPs interact with and permeabilize the OM. This effort will be useful for clarifying the peptide parameters for optimized activity against Gram-negative bacteria, which are an increasingly serious source of infection. Polymer brushes grafted membranes are relevant in a variety of contexts such as the outer LPS layer of the OM and glycoproteins grafted to membranes. We plan on studying how a polymer brush alters the interactions between particles embedded in the brush, focusing on the possibility of brush-induced attractions between the imbedded particles. The outcome of this study will offer a conceptual framework for understanding the observed clustering of integrin proteins on cancerous cell membranes with bulky glycoproteins grafted to their surfaces and likely stimulate a further investigation into the glycoproteins or other molecular components as therapeutic targets. Our proposal will offer the trainees a solid background for working across physics, computational modeling, and biomedical applications.