We propose the development of computational tools that promote the progress of antimicrobial peptide engineering. Drug-resistant pathogens are becoming a significant public health concern. The prolific use of antibiotics in the last few decades inevitably increased the bacterial species with resistance. Antimicrobial peptides (AMPs), recognized as potent components of eukaryotic innate immune response mechanisms, appear to be promising therapeutic anti-pathogen agents. A wide array of experiments suggests a complex interplay between the bacterial cell envelope components and the peptides. However, how exactly AMPs modulate membrane structure remains largely unclear. We leverage the high resolution, atomic level picture of molecular dynamics simulations, to understand the interactions of AMPs with bacterial and mammalian membranes. We also develop data mining algorithms that identify recurring sequence and structural patterns in known, naturally occurring AMPs. Importantly, active collaborations with leading research groups in the areas of antimicrobial peptides and peptide/membrane interactions provide the necessary feedback mechanism for validation and refinement of computational results. The three specific aims of this project are: 1. Quantify the interactions between AMPs and mammalian, bacterial and viral model membranes using high productivity computer simulations. 2. Recognize the sequence/structural elements that are responsible for cathelicidin and minidefensin antimicrobial activity 3. Establish a process of feedback mechanisms between experiments, computer models and new experimental design in order to promote rational peptide engineering. Experimentally investigate novel peptides based on model-driven design rules.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM070989-02
Application #
7102741
Study Section
Special Emphasis Panel (ZRG1-BDMA (01))
Program Officer
Wehrle, Janna P
Project Start
2005-08-01
Project End
2010-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$220,518
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Kaznessis, Yiannis N (2014) Multiscale Models of Antibiotic Probiotics. Curr Opin Chem Eng 6:18-24
Volzing, Katherine; Borrero, Juan; Sadowsky, Michael J et al. (2013) Antimicrobial peptides targeting Gram-negative pathogens, produced and delivered by lactic acid bacteria. ACS Synth Biol 2:643-50
Bolintineanu, Dan S; Vivcharuk, Victor; Kaznessis, Yiannis N (2012) Multiscale models of the antimicrobial peptide protegrin-1 on gram-negative bacteria membranes. Int J Mol Sci 13:11000-11
Vivcharuk, Victor; Kaznessis, Yiannis N (2011) Thermodynamic analysis of protegrin-1 insertion and permeation through a lipid bilayer. J Phys Chem B 115:14704-12
Bolintineanu, Dan S; Kaznessis, Yiannis N (2011) Computational studies of protegrin antimicrobial peptides: a review. Peptides 32:188-201
Volzing, Katherine; Biliouris, Konstantinos; Kaznessis, Yiannis N (2011) proTeOn and proTeOff, new protein devices that inducibly activate bacterial gene expression. ACS Chem Biol 6:1107-16
Langham, Allison; Kaznessis, Yiannis N (2010) Molecular simulations of antimicrobial peptides. Methods Mol Biol 618:267-85
Vivcharuk, Victor; Kaznessis, Yiannis (2010) Free energy profile of the interaction between a monomer or a dimer of protegrin-1 in a specific binding orientation and a model lipid bilayer. J Phys Chem B 114:2790-7
Bolintineanu, Dan; Hazrati, Ehsan; Davis, H Ted et al. (2010) Antimicrobial mechanism of pore-forming protegrin peptides: 100 pores to kill E. coli. Peptides 31:1-8
Vivcharuk, Victor; Kaznessis, Yiannis N (2010) Dimerization of protegrin-1 in different environments. Int J Mol Sci 11:3177-94

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