Antimicrobial peptides provide natural defense against microbial infection and thus hold promise as the basis of new antibiotics. Substantial evidence suggests that they target the bacterial membranes, by either forming pores or disintegrating them. However, an understanding of this process to the level of predicting the behavior of specific peptides is lacking. Over the last few years the PI?s group used novel implicit membrane modeling, as well as detailed all-atom simulations, to obtain significant insights into the function of these peptides. The PI now aims to use a multipronged approach that encompasses all-atom simulations, implicit-solvent simulations, and molecular thermodynamic modeling, to develop a systematic approach that predicts the structure of peptide-stabilized membrane pores. Close interaction with experimental labs will help validate the predicted models. This work has three aims. The first focuses on the ?-hairpin antimicrobial peptide protegrin, and aims to elucidate whether it forms complete ?-barrels, incomplete barrels (arcs), or classical toroidal pores. Electrophysiology, dye leakage, and antimicrobial activity measurements will be used to validate the theoretical results. The other two aims provide key elements in a comprehensive theory of peptide-induced membrane pore formation: peptide-peptide interactions and the free energy of membrane deformation. The extent of interactions between peptides in the process of pore formation is a crucial unsolved problem. The PI?s group will first validate the implicit solvation models by comparison to experiments and explicit simulation potentials of mean force and then proceed to characterize the extent of aggregation of melittin and magainin on membrane surfaces and in pores. Mixtures of magainin with PGLa will also be considered to address the observed synergy between these two peptides.
The third aim i s to include in the theory the free energy of membrane deformation. The free energy of a peptide-stabilized pore contains contributions from peptide-pore interactions, peptide-peptide interactions and membrane deformation. Pore structure is characterized by four properties: size, shape, headgroup distribution, and charge distribution in mixed membranes. All-atom simulations will be used to obtain data that will parameterize an analytical function of these four properties. This function, together with implicit-solvent simulations, will be used to determine profiles of free energy as a function of radius and lowest free energy peptide-pore structures. The resulting structures will be tested by all-atom simulations. The pore structure of different peptides in neutral and charged membranes should provide a definitive answer to the origin of the difference in selectivity between melittin and magainin and a firm basis for the design of peptides or peptidomimetics with high potency and low toxicity.

Public Health Relevance

Antimicrobial peptides are naturally produced by a wide range of organisms, including humans, as defense against microbial infection. However, their mechanism of action is not well understood. There is broad consensus that they attack the bacterial membrane, but no reliable method is available for predicting the efficacy of a given peptide. This work aims to understand how peptides stabilize pores in biological membranes, using a combination of theoretical methods guided and tested by experimental measurements. Success in this effort could open the door to the design of novel antibiotics, which are sorely needed given the growth of microbial resistance to currently used antibiotics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Nie, Zhongzhen
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City College of New York
Schools of Arts and Sciences
New York
United States
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Pino-Angeles, Almudena; Lazaridis, Themis (2018) Effects of Peptide Charge, Orientation, and Concentration on Melittin Transmembrane Pores. Biophys J 114:2865-2874
Lipkin, Richard; Lazaridis, Themis (2017) Computational prediction of the optimal oligomeric state for membrane-inserted ?-barrels of protegrin-1 and related mutants. J Pept Sci 23:334-345
Lazaridis, Themis; Hummer, Gerhard (2017) Classical Molecular Dynamics with Mobile Protons. J Chem Inf Model 57:2833-2845
Lipkin, Richard; Lazaridis, Themis (2017) Computational studies of peptide-induced membrane pore formation. Philos Trans R Soc Lond B Biol Sci 372:
Lipkin, Richard; Pino-Angeles, Almudena; Lazaridis, Themis (2017) Transmembrane Pore Structures of ?-Hairpin Antimicrobial Peptides by All-Atom Simulations. J Phys Chem B 121:9126-9140