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A Molecular Dynamics Simulation-Isothermal Titration Calorimetry Study of Antimicrobial Peptide-Peptide Interaction

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Title: A Molecular Dynamics Simulation-Isothermal Titration Calorimetry Study of Antimicrobial Peptide-Peptide Interaction
Author: Vafaei, Shaghayegh
Department: Department of Physics
Program: Biophysics
Advisor: Gray, Chris G.Tomberli, Bruno L.
Abstract: Increasing demand for antibiotics, and increasing antibiotic resistance, have led to the investigation of possible novel antibiotics by many researchers. For this purpose, experimental and theoretical studies have been carried out to draw scientists’ attention to antimicrobial peptides and their interaction with the surface of bacterial membranes. Their ability to disrupt the functioning of bacterial membranes has been probed from different perspectives. The most desirable antimicrobial peptides are those which do not harm plant or animals’ membranes but which disrupt bacterial membranes. It has been found that some cationic antimicrobial peptides (CAMPs) satisfy these requirements. CAMPs interacting with the outer membrane of gram-negative bacteria and the membrane of gram-positive bacteria have been studied recently. We conduct a Molecular Dynamics simulation study of peptide-peptide interactions in physiological solutions and investigate the mechanism of CAMPs aggregation, since aggregation of the peptides could precede their interaction with the membrane. Different algorithms are applied to calculate the potential mean force of the aggregation process of peptides to select the most efficient one. Also, we have run isothermal titration calorimetry (ITC) experiments to measure the peptide-peptide binding enthalpy. The particular CAMP studied is HHC-36, a peptide selected by high throughput screening which has nine amino acid residues and charge +5 in natural units. We examined our chosen simulation techniques, i.e., the OFR and the FR methods, analysis methods, i.e., bincrossing and binpassing methods, and with a toy model of sodium-sodium in bulk water observed attractive interactions between two similarly charged ions. We proposed a simpler version of McMillan-Mayer theory of solution using a semi-grand canonical ensemble. We extended the theory and derived the enthalpy second virial coefficient from the semi-grand osmotic second virial coefficient and linked the MD simulation results to the ITC experimental results. We found a good agreement between the theoretical and the experimental values of the osmotic pressure second virial coefficient and the enthalpy second virial coefficients for the system of binary benzene-benzene in water. We carried out a series of MD simulations to calculate the PMF of HHC-36 binary peptide-peptide interactions in water at the two temperatures of 295 and 325 K, extracted the osmotic pressure second virial coefficients, and estimated the theoretical enthalpy second virial coefficient, which has factor of 40 discrepancy from the experimental enthalpy second virial coefficient obtained from the ITC experiments. Studies have shown that the ITC experiments have statistical errors caused by the ITC machine which we do not have the option to change. On the theoretical side, we hope to reduce the discrepancy between theory and experiment by reducing the simulation statistical error bars, by performing longer simulation runs and enhancing the sampling.
Date: 2015-01
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