Biological membranes function as an essential barrier between living cells and their environments. The membrane associated peptides interact with membrane either to facilitate the energy and materials exchange between the environments and cytoplasm, or to break the membrane and cause the deadly membrane leakage. The activity and the structures of these peptides are essential to screen the drug candidates. However, the lack of atomic details in membrane-bound structures and their interactions with cell membranes leads to the difficulty in better understanding of the biological role of membrane associated peptides in their mechanisms. Through this study, we develop packing energy minimization methods and potential mean force (PMF) coarse-grained MD simulations to obtain the peptides aggregates and to measure the free energy required to transfer the peptides from bulk water phase to water-membrane interface to bilayer interior. Biological activity (i.e. antimicrobial or cytolitic) appears to be closely related to the trans-membrane ability and the PMF profile can be an instructive index to identify the activity of designed and existing membrane associated peptides. The molecular level understanding of the relationship between structure and biological effect on AMP trans-membrane activity can be obtained, which is important in the development of therapeutic drugs.  Moreover, the statistics tools (Quantitative structure�activity relationship, i.e. QSAR) were also applied in this work as the first-level screening tools, which can effectively reduce the computational expenses. All these advantages make the method an excellent high-throughput method for drug candidate discovery and evaluation.

High-throughput computational screening methods for membrane associated peptide based drug candidates discovery and evaluation

246th National Meeting (2013)

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