Antimicrobial peptides (AMPs) are small, usually cationic, amphipathic peptides that provide a first host defense mechanism for species in all kingdoms by permeabilizing the membrane of pathogenic organisms. Their positive charge is thought to afford them higher affinity for the negatively charged bacterial membranes relative to the neutral outer leaflet of mammalian membranes. However, their mechanism of action and structural determinants of activity are still unclear. Over the last two years our lab developed unique modeling tools that take into account the membrane environment implicitly, include the effect of anionic lipids and ionic strength, allow for the presence of an aqueous pore, and incorporate the effect of transmembrane voltage. We propose to apply these methods to gain insights into the mechanism of action of AMPs.
The specific aims are: 1. Characterize membrane adsorption of AMPs and seek correlations with activity and selectivity, i.e. determine the membrane bound configuration and membrane binding energy of a large number of AMPs as a function of membrane charge and ionic strength and correlate these to the observed experimental properties of the peptides, such as antimicrobial spectrum. These studies will test the hypothesis that electrostatics is a major determinant of target selectivity. 2. Investigate mechanisms of membrane permeabilization by AMPs. We will build models of barrel-stave pores, toroidal pores, and transmembrane beta barrels and compare the free energy of their formation. We make the novel hypothesis that the imperfect amphipathicity of many antimicrobial peptides makes them bind toroidal membrane pores more strongly than flat membrane surfaces. 3. Testing of the models and rational design of improved AMPs. Sequence modifications will be proposed towards peptides that are less toxic, more potent, and more active at lower concentrations and higher ionic strength. Collaborations with leading experimental groups will allow us to put our designs to a practical test. Significance: Understanding the mechanism of action of AMPs could lead to the discovery of new antibiotics. Public Health Relevance: This project aims to understand the mechanism of action of antimicrobial peptides, small peptides that provide a first host defense mechanism for species in all kingdoms by permeabilizing the membrane of pathogenic organisms. This will be accomplished by computational studies of their binding to membranes and membrane pores. The results will be used to rationally design improved versions of these peptides that could be used as novel antibiotics.

Public Health Relevance

This project aims to understand the mechanism of action of antimicrobial peptides, small peptides that provide a first host defense mechanism for species in all kingdoms by permeabilizing the membrane of pathogenic organisms. This will be accomplished by computational studies of their binding to membranes and membrane pores. The results will be used to rationally design improved versions of these peptides that could be used as novel antibiotics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Enhancement Award (SC1)
Project #
5SC1AI084899-04
Application #
8241062
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (CH))
Program Officer
Ritchie, Alec
Project Start
2009-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$261,491
Indirect Cost
$89,973
Name
City College of New York
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
603503991
City
New York
State
NY
Country
United States
Zip Code
10031
Prieto, Lidia; He, Yi; Lazaridis, Themis (2014) Protein arcs may form stable pores in lipid membranes. Biophys J 106:154-61
Rahaman, Asif; Lazaridis, Themis (2014) A thermodynamic approach to alamethicin pore formation. Biochim Biophys Acta 1838:98-105
Yuzlenko, Olga; Lazaridis, Themis (2013) Membrane protein native state discrimination by implicit membrane models. J Comput Chem 34:731-8
Prieto, Lidia; Lazaridis, Themis (2011) Computational studies of colicin insertion into membranes: the closed state. Proteins 79:126-41
Mihajlovic, Maja; Lazaridis, Themis (2010) Antimicrobial peptides in toroidal and cylindrical pores. Biochim Biophys Acta 1798:1485-93
Mihajlovic, Maja; Lazaridis, Themis (2010) Antimicrobial peptides bind more strongly to membrane pores. Biochim Biophys Acta 1798:1494-502