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Download fileA Molecular Dynamics Study of the Short-Helical-Cytolytic Peptide Assembling and Bioactive on Membrane Interface
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posted on 2017-07-22, 00:00 authored by Fude Sun, Xiufang Ding, Lida Xu, Jun F. Liang, Long Chen, Shi-Zhong LuoCytolytic
peptides (CPs) have long been employed as broad-spectrum
antibiotic agents to overcome multidrug resistance. However, the development
of novel peptide drugs is still limited by the elusive molecular understanding
of the membrane-lysis mechanism and modeling of CPs, especially of
the short helical species. In this study, a known anticancer CP named
PTP-7b (FLGALFKALSHLL) in disrupting membranes via self-assembling
approach was studied by combining experiments and time-extended coarse-grained
dynamic simulations. Effective membrane disintegration was induced
by aggregation of the membrane-bound peptide individuals, rather than
the preassembled peptide clusters. The disturbance level of lipid
bilayers depended on the peptide concentrations, which was responsible
for the long time-costing of PTP-7b in killing cells. On the basis
of lines of simulations and energy-landscape calculations, the dynamics
of membrane deformation evolving toward preliminary leakage resulted
from the aggregated PTP-7b was demonstrated, which was subjected to
the spatiotemporal cooperation of the membrane-inserted and the periplasmic
peptides. The molecular mechanism incorporated the 11th histidine
interaction coupled with the peptide amphiphilicity in accelerating
phospholipid migration outward. This study revealed elaborate modeling
and dynamics information about the short helical CPs in membrane lysis,
which would be helpful to understand the underlying mechanisms and
rational design of CPs for drug application.