TARGETING PROTEIN INTERACTIONS AND DESIGNING CHIMERIC PROTEINS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们正在严格评估针对蛋白质/蛋白质界面的虚拟筛选协议，并开发提高分子对接速度和准确性的方法。特别是，其中一个重点是系统搜索算法的开发。分子对接中使用的大多数构象搜索方法都是从遗传或蒙特卡罗算法1，2与能量估计紧密结合来确定玻尔兹曼加权选择的。这些随机方法没有全面地搜索构象空间，并且可能会错过评估关键的低能量姿势。系统搜索详尽地采样了配体相对于受体的构象、旋转和平移自由度。由于采样构象自由度所需的计算爆炸，系统搜索方法的使用历来是避免的。我们开发了一种方法SKATE，它只对配体的相关对接空间进行分析采样，以最大限度地减少计算复杂性。未来的发展将集中在进一步的算法和代码优化上，以增强对接中系统搜索的功能。此外，REMD正被用于评估具有半刚性二级结构模拟的嵌合蛋白质的增强的稳定性。

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.