Physical Chemistry Seminar: The story of an anticancer peptide: Experiments and simulations

Zoom: https://tau-ac-il.zoom.us/j/87820055721?pwd=kewAaVRPgfvQXtUuQD41aWPtcLcecQ.1

Abstract:

Material transport across the boundary of a cell or a cell compartment is necessary to sustain life. Biological machines (channels and pumps) translocate matter across biological membranes selectively and efficiently. However, this is only one permeation mechanism. An alternative method of crossing cellular boundaries is passive transport. Molecules may permeate phospholipid membranes directly and without the assistance of biological energy or transport machinery. The cell-penetrating peptides (CPP) are molecular agents that passively pass across biological membranes. Since discovering the TAT peptide of HIV, which assists in virus permeation to the cell, thousands of different CPPs have been recorded. CPPs are promising for medical applications. However, their weak membrane selectivity is a concern. Here, we focus on one CPP, an anticancer peptide, NAF-144-67, with a unique origin and function. It is highly selective. It does not permeate normal cells but enters into and kills breast cancer cells.

To understand the function of NAF-144-67, we conducted atomically detailed simulations of the permeation event. The prime challenge for the calculations is the time scale. The permeation of NAF-144-67 takes seconds to hours, while the integration time step is a femtosecond (10-15 s). I will describe the exact computational approach and theory we developed to address the time scale challenge (Milestoning) and the application to NAF-144-67 permeation.

In addition to experiments in living cells and to gain further physical chemistry insight, I will discuss experiments and simulations of peptide permeation across membranes of simple synthetic vesicles that mimic cancer and normal cells. I will describe an atomistic mechanism that makes it possible for the peptide to permeate selectively to cancer cells but not normal cells. Confocal microscopy, spectroscopy experiments, and Milestoning simulations of the permeation events support this mechanism.
 

Seminar Organizer: Dr. Barak Hirshberg