TARGETING PROTEIN INTERACTIONS AND DESIGNING CHIMERIC PROTEINS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们正在严格评估针对蛋白质/蛋白质界面的虚拟筛选方案，并开发方法以提高分子对接的速度和准确性。特别是，一个重点是系统搜索算法的发展。分子对接中使用的大多数构象搜索方法来自遗传或蒙特卡罗算法1，2与能量估计紧密耦合，以确定玻尔兹曼加权选择。这些随机方法没有全面搜索构象空间，并且可能错过评估关键的低能量姿态。系统搜索详尽的样品配体构象，旋转和平移自由度相对于受体。由于对构象自由度进行采样所需的计算爆炸，系统搜索方法的使用在历史上一直被避免。我们开发了一种方法SKATE，仅对配体的相关对接空间进行分析采样，以最大限度地降低计算复杂性。未来的发展将集中在进一步的算法和代码优化，以提高对接系统搜索的功能。此外，REMD被用来估计增强稳定性的嵌合蛋白质与半刚性二级结构模拟物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are critically evaluating virtual screening protocols targeting protein/protein interfaces and developing methods to improve the speed and accuracy of molecular docking. In particular, one focus is the development of systematic search algorithms. Most conformational search methods used in molecular docking are derived from genetic or Monte Carlo algorithms1,2 tightly coupled with an energy estimate to determine Boltzmann-weighted selection. These stochastic methods do not comprehensively search conformational space, and can miss evaluating critical low-energy poses. Systematic search exhaustively samples a ligands conformation, rotational, and translational degrees of freedom with respect to the receptor. The use of systematic search methods has historically been avoided due to the computational explosion required for sampling conformational degrees of freedom. We have developed a method SKATE that analytically samples only the relevant docked space of the ligand to minimize the computational complexity. Future development will focus on further algorithmic and code optimization to enhance the functionality of systematic search in docking.In addition REMD is being used to estimate enhanced stability in chimeric proteins with semi-rigid secondary structure mimetics.