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The pH-Low Insertion Peptide (pHLIP) is an acid-sensitive peptide that binds to the cell membrane surface and under acidic conditions, can then fold and insert into the membrane. The mechanism for binding of this peptide is poorly understood, but has direct implications for long-term development of pHLIP for applications in diagnostic imaging and targeted delivery of drugs. Using several approaches with molecular dynamics (MD) simulations, we show that the Wimley-White scale of partitioning free energies can be used to inform the propensity for pHLIP to bind to a model bilayer surface. In addition, MD simulations are necessary to provide the context for the dynamics of the peptide-bilayer complex, most notably formation of secondary structural elements that are a hallmark of pHLIP insertion. Theory and modeling together provide a comprehensive picture of the behavior of pHLIP at the cell membrane surface. Host: Chris Neale |