Modeling Membrane Active Peptides with Implicit Membrane models
Item
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Title
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Modeling Membrane Active Peptides with Implicit Membrane models
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Identifier
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d_2009_2013:8f26e6e7ac6f:11784
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identifier
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12447
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Creator
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He, Yi,
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Contributor
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Themis Lazaridis
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Date
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2013
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biophysics | Biochemistry | Antimicrobial Peptides | Implicit Membrane Model | Membrane Active Peptides | Molecular Dynamics | Transmembrane Peptides
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Abstract
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Membranes are the natural barriers of all cellular organisms. They separate the inner environment from the outer environment. They also divide cell contents into different functional compartments. Many membrane active peptides, however, challenge the function of membranes. They translocate through, form pores inside, or even break down the membranes. Understanding their mechanisms will help us design better drugs.;Molecular dynamics (MD) provides a unique way to study these peptides at small time scales. A lot of useful information can therefore be determined: such as, peptide orientation, structure adjustment, insertion into the membrane, and binding energy. Implicit membrane models are particularly useful because their low computational cost allows us to study peptides at longer time scales or larger numbers.;The object of the thesis is to study the membrane active peptides using implicit membrane models. The study is focused on three areas: 1) We first examined the transmembrane peptide orientation in both implicit and explicit MD simulations. Using theoretical methods, we tried to explain the gap between the tilt angles predicted by hydrophobic mismatching theory and the ones determined by 2H NMR experiments. 2) To study the interaction between cationic peptides and anionic pores, we extended the current implicit pore model to anionic membranes. This model was applied to two typical antimicrobial peptides---magainin and melittin---and was used to explain their different preferences for anionic lipid fractions. We also evaluated the stability of three protegrin octameric pore models using this model. 3) We then tried to determine the link between binding affinity to membrane surface and biological activities of antimicrobial peptides. We found that both the experimental binding free energy and the theoretical transfer energy correlate with the biological activities, although the correlation is weak. Many other factors may also affect the biological activities of antimicrobial peptides. Moreover, based on a critical evaluation of "carpet" model, we found that most peptides would show higher activity than the prediction of the "carpet" model. The deviation of their biological activities from the "carpet" model correlates with their transfer energies to pores. The knowledge we gained from this study can help us establish quantitative models for predicting antimicrobial peptide activities.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biochemistry
