Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
Materials Science and Engineering, University of California, San Diego, La Jolla, CA, USA.
Nat Chem. 2018 Jul;10(7):732-739. doi: 10.1038/s41557-018-0053-4. Epub 2018 Apr 30.
De novo design and construction of stimuli-responsive protein assemblies that predictably switch between discrete conformational states remains an essential but highly challenging goal in biomolecular design. We previously reported synthetic, two-dimensional protein lattices self-assembled via disulfide bonding interactions, which endows them with a unique capacity to undergo coherent conformational changes without losing crystalline order. Here, we carried out all-atom molecular dynamics simulations to map the free-energy landscape of these lattices, validated this landscape through extensive structural characterization by electron microscopy and established that it is predominantly governed by solvent reorganization entropy. Subsequent redesign of the protein surface with conditionally repulsive electrostatic interactions enabled us to predictably perturb the free-energy landscape and obtain a new protein lattice whose conformational dynamics can be chemically and mechanically toggled between three different states with varying porosities and molecular densities.
从头设计和构建能够在离散构象状态之间进行预测性切换的响应性蛋白质组装体仍然是生物分子设计中的一个重要但极具挑战性的目标。我们之前报道了通过二硫键相互作用自组装的合成二维蛋白质晶格，这赋予了它们独特的能力，可以在不失去晶体秩序的情况下进行连贯的构象变化。在这里，我们进行了全原子分子动力学模拟，以绘制这些晶格的自由能景观，通过电子显微镜进行了广泛的结构特征验证，并确定其主要由溶剂重组熵控制。随后对蛋白质表面进行条件性排斥静电相互作用的重新设计，使我们能够预测性地扰乱自由能景观，并获得一种新的蛋白质晶格，其构象动力学可以通过化学和机械方式在三种不同状态之间切换，具有不同的孔隙率和分子密度。
