Cline, Tyler NewmanSince the discovery of Penicillin in 1928 by Sir Alexander Fleming, antibiotics have been one of the most important technologies in modern medicine. Due to the lack of novel innovative methods and the gross abuse of antibiotics both in human use and agriculture, we currently face an antibiotic resistance crisis. In the last fifty years only a handful of new class of antibiotics that target gram-positive bacteria have been introduced and, in that time, no new class of antibiotics that target gram-negative bacteria have been introduced. This thesis focuses on the molecular dynamic simulations involving the cationic α-helical antibacterial peptide, WLBU2-mod (RRWVRRVRRVWRRVVRVVRRWVRR), binding with a gram-negative bacterial inner membrane (IM) mimic composed of palmitoyloleoyl PE (POPE), palmitoyloleoyl PG (POPG), and 1,1’,2,2’-tetraoctadecenoyl CL (TOCL2) in a 7:2:1 ratio respectively. The structure of WLBU2-mod was predicted using Robetta to be either a single extended α-helical structure or a bent α-helical structure. Replica exchange with solute tempering with an improved Hamiltonian acceptance protocol (REST2) was performed on WLBU2-mod to relax the peptide to an unstructured conformation in an ii explicit aqueous solution. WLBU2-mod relaxed with REST2 consists of mainly random coil and β-sheet secondary structure which matches experimental circular dichroism (CD) results collected by Aria Salyapongse and Dr. Tristram-Nagle. Experimental CD results with the IM predicted the peptide to be structured with majority α-helical secondary structure, contrary to the unstructured results of the peptide in water. Both structured and unstructured WLBU2-mod were placed in parallel 10 Å above the IM mimic and molecular dynamics (MD) was performed to observe the binding mechanism. Simulations failed to see significant bilayer thinning or penetration into the hydrophobic core but there is strong indication that our simulations represent in intermediate state toward the final binding mechanism. In order to observe more substantial binding to the IM, future projects should consider increasing the length of the simulations and flipping the orientation of the peptide to have the hydrophobic components face inward toward the bilayer. Future projects in combination with the groundwork laid out here will hopefully provide insight into how antibacterial peptides can become the answer to the resistance crisis we face today.enThesisChemical engineeringAntibacterial peptideAntimicrobial peptideMolecular dynamicsReplica exchangeREST