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LEADER 04288cam a2200517Ia 4500

001 ocn824510495;

003 OCoLC;

005 20141212050733.0;

006 m o d ;

007 cr bn|||||||||;

008 130116s2012 ncua ob 000 0 eng d;

035 a| (Sirsi) o824510495;

035 a| (OCoLC)824510495;

049 a| EREE;

090 a| QR177;

100 1 a| Clark, Tiffany D.?| UNAUTHORIZED;

245 10 a| Elucidating the mechanism of action of unnatural amino acid containing antimicrobial peptides in membrane environments /c| by Tiffany D. Clark.;

260 a| [Greenville, N.C.] :b| East Carolina University,c| 2012.;

300 a| 321 pages :b| illustrations (some color), digital, PDF file;

336 a| text2| rdacontent;

337 a| computer2| rdamedia;

338 a| online resource2| rdacarrier;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| Ph.D.c| East Carolina Universityd| 2012.;

500 a| Presented to the faculty of the Department of Chemistry.;

500 a| Advisor: Rickey Hicks.;

500 a| Title from PDF t.p. (viewed Jan. 23, 2013).;

520 3 a| Organism resistance continues to develop to the currently available antimicrobial compounds necessitating the development of innovative new therapeutic compounds with different specificities and mechanisms of action that provide acceptable therapeutic indices. Unnatural amino acid containing antimicrobial peptides could provide a novel avenue for the development of therapies with improved efficacy and pharmacokinetics over natural amino acid containing peptides which are prone to protease degradation. Molecular dynamics (MD) simulations of antimicrobial peptides containing unnatural amino acids have been performed using explicit water and multiple model membrane types in all-atom simulations. The structural properties of peptides were investigated using both the canonical and isothermal-isobaric ensembles to further understand the mechanism through which the collections of AMPs exert their in vitro activity. Simulations with micelle membrane models were conducted at 300 K to correlate with experimental circular dichroism (CD) data showing the secondary structure the peptides adopt in the presence of an electrostatic membrane model. Analysis of the stabilized MD trajectory reflects peptide structural consistency with experimental data. Simulations of the peptides with bilayer model membranes were conducted at the physiologically relevant 310 K to correlate with experimental cellular activity data which demonstrated the antimicrobial activity of the peptides without providing insight into the mechanism through which the activity was achieved. Long time scale simulations have noted distinct differences between bilayers in the presence of AMPs as compared to those without the peptide. Mixed bilayers with an anionic charge modeled bacterial membranes while a confluent zwitterionic bilayer modeled the mammalian membrane. This research has demonstrated that force field parameters for unnatural amino acids can be derived from QM calculations. FF parameters derived from structures identified from a DFT approach have also been used to expand the AMBER ff03 force field. The FF parameters were able to able to model the interaction of the peptides which contain unnatural amino acids. The data is consistent with NMR data and further supported with CD spectroscopy.;

504 a| Includes bibliographical references.;

650 0 a| Drug resistance in microorganisms.=| ^A718;

650 0 a| Peptide antibiotics.=| ^A1056932;

650 0 a| Amino acids.=| ^A6734;

653 a| Chemistry;

653 a| Biophysics;

653 a| Pharmaceutical sciences;

700 1 a| Hicks, Rickey P.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Chemistry.?| UNAUTHORIZED;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/4072;

949 o| jgml;

994 a| C0b| ERE;

596 a| 1 4;

998 a| 3255358;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 3255358-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 1/16/2013x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 3255358-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 1/16/2013x| ETDz| HERESOURCE;

Elucidating the mechanism of action of unnatural amino acid containing antimicrobial peptides in membrane environments / by Tiffany D. Clark.

Author/creator	Clark, Tiffany D.
Other author	Hicks, Rickey P.
Other author	East Carolina University. Department of Chemistry.
Format	Theses and dissertations
Publication Info	[Greenville, N.C.] : East Carolina University, 2012.
Description	321 pages : illustrations (some color), digital, PDF file
Supplemental Content	Access via ScholarShip
Subjects	Drug resistance in microorganisms. Peptide antibiotics. Amino acids.

Summary	Organism resistance continues to develop to the currently available antimicrobial compounds necessitating the development of innovative new therapeutic compounds with different specificities and mechanisms of action that provide acceptable therapeutic indices. Unnatural amino acid containing antimicrobial peptides could provide a novel avenue for the development of therapies with improved efficacy and pharmacokinetics over natural amino acid containing peptides which are prone to protease degradation. Molecular dynamics (MD) simulations of antimicrobial peptides containing unnatural amino acids have been performed using explicit water and multiple model membrane types in all-atom simulations. The structural properties of peptides were investigated using both the canonical and isothermal-isobaric ensembles to further understand the mechanism through which the collections of AMPs exert their in vitro activity. Simulations with micelle membrane models were conducted at 300 K to correlate with experimental circular dichroism (CD) data showing the secondary structure the peptides adopt in the presence of an electrostatic membrane model. Analysis of the stabilized MD trajectory reflects peptide structural consistency with experimental data. Simulations of the peptides with bilayer model membranes were conducted at the physiologically relevant 310 K to correlate with experimental cellular activity data which demonstrated the antimicrobial activity of the peptides without providing insight into the mechanism through which the activity was achieved. Long time scale simulations have noted distinct differences between bilayers in the presence of AMPs as compared to those without the peptide. Mixed bilayers with an anionic charge modeled bacterial membranes while a confluent zwitterionic bilayer modeled the mammalian membrane. This research has demonstrated that force field parameters for unnatural amino acids can be derived from QM calculations. FF parameters derived from structures identified from a DFT approach have also been used to expand the AMBER ff03 force field. The FF parameters were able to able to model the interaction of the peptides which contain unnatural amino acids. The data is consistent with NMR data and further supported with CD spectroscopy.
General note	Presented to the faculty of the Department of Chemistry.
General note	Advisor: Rickey Hicks.
General note	Title from PDF t.p. (viewed Jan. 23, 2013).
Dissertation note	Ph.D. East Carolina University 2012.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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Elucidating the mechanism of action of unnatural amino acid containing antimicrobial peptides in membrane environments / by Tiffany D. Clark.

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