Sun Hao, Qiao Baofu, Choi Wonmin, Hampu Nicholas, McCallum Naneki C, Thompson Matthew P, Oktawiec Julia, Weigand Steven, Ebrahim Omar M, de la Cruz Monica Olvera, Gianneschi Nathan C
Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States.
Department of Chemistry and Chemical & Biomedical Engineering, University of New Haven, West Haven, Connecticut 06516, United States.
ACS Cent Sci. 2021 Dec 22;7(12):2063-2072. doi: 10.1021/acscentsci.1c01149. Epub 2021 Dec 2.
Peptide-brush polymers (PBPs), wherein every side-chain of the polymers is peptidic, represent a new class of proteomimetic with unusually high proteolytic resistance while maintaining bioactivity. Here, we sought to determine the origin of this behavior and to assess its generality via a combined theory and experimental approach. A series of PBPs with various polymer backbone structures were prepared and examined for their proteolytic stability and bioactivity. We discovered that an increase in the hydrophobicity of the polymer backbones is predictive of an elevation in proteolytic stability of the side-chain peptides. Computer simulations, together with small-angle X-ray scattering (SAXS) analysis, revealed globular morphologies for these polymers, in which pendant peptides condense around hydrophobic synthetic polymer backbones driven by the hydrophobic effect. As the hydrophobicity of the polymer backbones increases, the extent of solvent exposure of peptide cleavage sites decreases, reducing their accessibility to proteolytic enzymes. This study provides insight into the important factors driving PBP aqueous-phase structures to behave as globular, synthetic polymer-based proteomimetics.
肽刷聚合物（PBP），即聚合物的每个侧链都是肽链，代表了一类新型的蛋白质模拟物，具有异常高的抗蛋白水解能力，同时保持生物活性。在此，我们试图通过理论与实验相结合的方法来确定这种行为的起源，并评估其普遍性。制备了一系列具有不同聚合物主链结构的PBP，并检测了它们的蛋白水解稳定性和生物活性。我们发现，聚合物主链疏水性的增加预示着侧链肽的蛋白水解稳定性提高。计算机模拟以及小角X射线散射（SAXS）分析揭示了这些聚合物的球状形态，其中侧链肽在疏水作用的驱动下围绕疏水性合成聚合物主链凝聚。随着聚合物主链疏水性的增加，肽切割位点的溶剂暴露程度降低，减少了它们被蛋白水解酶作用的机会。这项研究深入了解了驱动PBP水相结构表现为球状、基于合成聚合物的蛋白质模拟物的重要因素。
