Date

2018

Department or Program

Chemistry

Primary Wellesley Thesis Advisor

Donald Elmore

Additional Advisor(s)

Mala Radhakrishnan

Abstract

Antimicrobial peptides (AMPs) are short, positively charged peptides with therapeutic potential against bacteria. Some AMPs function by translocating across bacterial cell membranes and targeting an intracellular component. One particularly potent translocating peptide, buforin II (BF2), is believed to target nucleic acids within the cell. An understanding of BF2 – DNA binding may lend itself to the design of more potent peptides. However, it is insufficient to study this binding under dilute buffer conditions, as is often done; the effect of other macromolecules, such as those present in intracellular environments, on BF2 – DNA binding must also be taken into account. Here, a range of computational models, where crowding is represented by a lowered solvent dielectric constant, spherical blobs, or lysozyme protein, are applied to frames extracted from molecular dynamics (MD) simulation. Analyses performed show that when crowders are represented explicitly as uncharged cavities or implicitly by a lowered solvent dielectric constant, particular buforin II cationic residues exhibit an increased contribution to binding in a crowded environment. The magnitude of this contribution decreases once charges are applied onto the crowders, resulting in a decreased contribution to binding for particular crowding models. The magnitude of this contribution to binding appears to be dependent on the particular crowding model, independent of charges on crowders. Analyses further suggest that crowder placement more greatly affects the robustness of calculations than whether the BF2 - DNA complex is extracted from a crowded or uncrowded simulation. In fact, random placement of crowders post-simulation was not able to adequately reproduce the electrostatic free energies calculated from simulation, electrostatics-driven, placement of crowders. These observations will help guide the models used by future work aimed at designing more potent peptides with enhanced nucleic acid binding.

Available for download on Wednesday, April 26, 2023

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