Membrane Pore Formation By Melittin Derivatives
BIOPHYSICAL JOURNAL(2020)
摘要
Pore formation on cell membranes by peptides or their synthetic mimics can have important medical and technological applications. Melittin, a well-studied 26-residue membrane-active peptide, has been the starting point for combinatorial library discovery of more potent peptides by Wimley, Hristova and coworkers. For instance, MelP5, derived by five mutations on melittin, is a better pore-former with activity at much lower concentration. The “macrolittins” are even more potent, forming macromolecule-size pores. Other combinatorially discovered peptides (pHD) are active only at low pH, while similar rationally designed peptides (e.g. MelP5_Δ6) have proven inactive. To obtain insights into the molecular origins of these differences, we have performed multi-microsecond molecular dynamics simulations of hexamers of five of the above peptides starting from transmembrane orientations in POPC. To emulate low pH, we protonate Asp, Glu and His residues, and, for highly acidic environment, the C-terminus as well. The size and the stability of the pore is used as a proxy for the potency of each peptide. We find that higher tilt angles, which give longer peptide projections on the xy plane, lead to a larger pore. Favorable interactions between adjacent peptides stabilize the pore, but interactions between non-adjacent peptides, usually with an unprotonated C terminus, lead to a smaller pore. The simulations are analyzed to determine the most important interactions that favor pore formation and could be used to propose new sequences for more potent peptides.
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关键词
membrane pore formation
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