Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, Brooklyn, New York11201, United States.
Center for Computational Biology, Flatiron Institute, New York, New York10010, United States.
Biomacromolecules. 2022 Nov 14;23(11):4851-4859. doi: 10.1021/acs.biomac.2c01031. Epub 2022 Oct 13.
The ability to engineer a solvent-exposed surface of self-assembling coiled coils allows one to achieve a higher-order hierarchical assembly such as nano- or microfibers. Currently, these materials are being developed for a range of biomedical applications, including drug delivery systems; however, ways to mechanistically optimize the coiled-coil structure for drug binding are yet to be explored. Our laboratory has previously leveraged the functional properties of the naturally occurring cartilage oligomeric matrix protein coiled coil (C), not only for its favorable motif but also for the presence of a hydrophobic pore to allow for small-molecule binding. This includes the development of Q, a rationally designed pentameric coiled coil derived from C. Here, we present a small library of protein microfibers derived from the parent sequences of C and Q bearing various electrostatic potentials with the aim to investigate the influence of higher-order assembly and encapsulation of candidate small molecule, curcumin. The supramolecular fiber size appears to be well-controlled by sequence-imbued electrostatic surface potential, and protein stability upon curcumin binding is well correlated to relative structure loss, which can be predicted by docking.
能够对自组装卷曲螺旋的溶剂暴露表面进行工程设计，可实现更高阶的分级组装，如纳米纤维或微纤维。目前，这些材料正在被开发用于一系列的生物医学应用，包括药物输送系统；然而，为了药物结合而对卷曲螺旋结构进行机械优化的方法还有待探索。我们实验室之前利用了天然存在的软骨寡聚基质蛋白卷曲螺旋（C）的功能特性，不仅因为其有利的基序，还因为存在疏水性孔允许小分子结合。这包括 Q 的开发，Q 是一种源自 C 的合理设计的五聚体卷曲螺旋。在这里，我们提出了一个由 C 和 Q 的母体序列衍生而来的、带有各种静电势的小蛋白微纤维文库，旨在研究候选小分子姜黄素的高阶组装和封装的影响。超分子纤维的尺寸似乎可以通过赋予序列的静电表面电势来很好地控制，并且姜黄素结合时的蛋白稳定性与相对结构损失密切相关，这可以通过对接来预测。
