Possible Pathway Into Cells
By analyzing two years of biocomputation and simulation, theoretical physicists at Rensselaer have uncovered what they believe is the long-sought-after pathway that an HIV peptide uses to enter healthy cells. Their discovery could help scientists treat other human illnesses by exploiting the same molecules that make HIV so deadly.
This research, published in the Proceedings of the National Academy of Science, is part of ongoing NSF-funded work by Angel Garcia, senior constellation professor in biocomputation and bioinformatics. Garcia has collaborations with J. Onuchic at the University of California at San Diego, Vijay Pande at Stanford University, and Catherine Royer at Montpellier, France. Garcia is studying pressure-induced changes in proteins using molecular simulations to establish a framework for understanding the role of water in protein function and stability.
For the last decade, scientists have known that a positively charged, 11-amino-acid chain of HIV (HIV-1 Tat protein) can cross through the cell membrane carrying a cargo. Researchers have proposed using the peptide to deliver genes for gene therapy and drugs directly to a cell. But despite many potential medical applications, the actual mechanism that opens the holes in the cell remained undiscovered.
Garcia and postdoctoral researcher Henry Herce showed that the peptide’s positive charge is what allows it to enter the cell. The HIV peptides are drawn to negative charges, and when an HIV peptide cannot satisfy itself with the negative charges available on the surface of a cell membrane, it reaches through the membrane to grab negatively charged groups in the molecules on the other side, opening a transient hole. This hole allows the flow of water and other material into the cell. Once all the peptides have been neutralized, the reaction stops and the hole closes, leaving behind a healthy, viable cell. Discovery of this mechanism illustrates the importance of membrane fluctuations, Garcia says.
Garcia’s computer cluster is now running simulations on the use of antimicrobial proteins that open a pore in the cell and keep it open, killing the cell. These proteins have promising direct applications for killing harmful cells in the body.
See also: Possible Pathway of HIV Revealed (Rensselaer Research Review)