TY - JOUR
T1 - Interactions between Membranes and "metaphilic" Polypeptide Architectures with Diverse Side-Chain Populations
AU - Lee, Michelle W.
AU - Han, Ming
AU - Bossa, Guilherme Volpe
AU - Snell, Carly
AU - Song, Ziyuan
AU - Tang, Haoyu
AU - Yin, Lichen
AU - Cheng, Jianjun
AU - May, Sylvio
AU - Luijten, Erik
AU - Wong, Gerard C.L.
N1 - This work is supported by grants from the National Science Foundation (DMR-1411329 to M.W.L. and G.C.L.W.; DMR-1610796 to M.H. and E.L.; DMR-1309525 to J.C.) and the National Institutes of Health (1R21AI117080 to J.C.). G.V.B. acknowledges a doctoral scholarship from CAPES Foundation/Brazil Ministry of Education (Grant No. 9466/13-4). Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393).
PY - 2017/3/28
Y1 - 2017/3/28
N2 - At physiological conditions, most proteins or peptides can fold into relatively stable structures that present on their molecular surfaces specific chemical patterns partially smeared out by thermal fluctuations. These nanoscopically defined patterns of charge, hydrogen bonding, and/or hydrophobicity, along with their elasticity and shape stability (folded proteins have Young's moduli of × 108 Pa), largely determine and limit the interactions of these molecules, such as molecular recognition and allosteric regulation. In this work, we show that the membrane-permeating activity of antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) can be significantly enhanced using prototypical peptides with "molten" surfaces: metaphilic peptides with quasi-liquid surfaces and adaptable shapes. These metaphilic peptides have a bottlebrush-like architecture consisting of a rigid helical core decorated with mobile side chains that are terminated by cationic or hydrophobic groups. Computer simulations show that these flexible side chains can undergo significant rearrangement in response to different environments, giving rise to adaptable surface chemistry of the peptide. This quality makes it possible to control their hydrophobicity over a broad range while maintaining water solubility, unlike many AMPs and CPPs. Thus, we are able to show how the activity of these peptides is amplified by hydrophobicity and cationic charge, and rationalize these results using a quantitative mean-field theory. Computer simulations show that the shape-changing properties of the peptides and the resultant adaptive presentation of chemistry play a key enabling role in their interactions with membranes.
AB - At physiological conditions, most proteins or peptides can fold into relatively stable structures that present on their molecular surfaces specific chemical patterns partially smeared out by thermal fluctuations. These nanoscopically defined patterns of charge, hydrogen bonding, and/or hydrophobicity, along with their elasticity and shape stability (folded proteins have Young's moduli of × 108 Pa), largely determine and limit the interactions of these molecules, such as molecular recognition and allosteric regulation. In this work, we show that the membrane-permeating activity of antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) can be significantly enhanced using prototypical peptides with "molten" surfaces: metaphilic peptides with quasi-liquid surfaces and adaptable shapes. These metaphilic peptides have a bottlebrush-like architecture consisting of a rigid helical core decorated with mobile side chains that are terminated by cationic or hydrophobic groups. Computer simulations show that these flexible side chains can undergo significant rearrangement in response to different environments, giving rise to adaptable surface chemistry of the peptide. This quality makes it possible to control their hydrophobicity over a broad range while maintaining water solubility, unlike many AMPs and CPPs. Thus, we are able to show how the activity of these peptides is amplified by hydrophobicity and cationic charge, and rationalize these results using a quantitative mean-field theory. Computer simulations show that the shape-changing properties of the peptides and the resultant adaptive presentation of chemistry play a key enabling role in their interactions with membranes.
KW - amphiphilic
KW - antimicrobial peptides
KW - cell-penetrating peptides
KW - membranes
KW - peptide membrane interactions
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U2 - 10.1021/acsnano.6b07981
DO - 10.1021/acsnano.6b07981
M3 - Article
C2 - 28212487
AN - SCOPUS:85016419564
SN - 1936-0851
VL - 11
SP - 2858
EP - 2871
JO - ACS Nano
JF - ACS Nano
IS - 3
ER -