MULTIRESOLUTION SAMPLING METHODS FOR PROTEIN & PEPTIDE CONFORMATIONAL SPACE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这个核心项目专注于混合模型的开发、验证和应用，旨在探索蛋白质和多肽折叠、配体对接和热力学方面的问题。AMBER99/GBSA潜在识别天然结构能量最低的能力及其与天然相似性的相关性在150个蛋白质上进行了评估，这些蛋白质是PDB200基准结构集的子集，代表PDB在41到200个残基之间。对于每种蛋白质，有14,000个诱饵，以前用Tasser产生。都是用过的。我们选择了50个蛋白质的子集进行2 ns的MD扩展运行。在只有33%的情况下，自然弹道快照在诱饵中具有最低的能量，并且自然-诱饵的平均能量差距为？22千卡/摩尔。此外，即使琥珀/GBSA势的相对权重被优化，琥珀/GBSA能量通常也不表现出与天然相似性的相关性，这是通过来自天然的RMSD来评估的。下一步，将测试不同版本的琥珀/GBSA力场，并将开发基于诱饵分析的提高潜力得分能力的方法。当仅用Amber/GBSA局部最小化诱饵时，集合中几乎所有的自然结构都被认为是最低能量结构，平均自然-诱骗能隙约为总自然能量的10%。为数不多的失败与蛋白质作为复合体的一部分结晶有关。在一个更困难的测试中，诱饵在300K下受到100ps的分子动力学松弛，然后最小化。现在，本征结构不是最低能量结构，琥珀/GBSA能量一般不表现出与本征相似性的相关性，这是通过与本征的均方根偏差来评估的。在接下来的一年里，将对整套PDB200进行评估，并对琥珀/GBSA力场进行优化。

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. This core project focuses on the development, validation, and application of hybrid models designed to explore aspects of protein and peptide folding, ligand docking and thermodynamics. The ability of the AMBER99/GBSA potential to recognize the native structure as being lowest in energy as well as its correlation with native-likeness was assessed on 150 proteins, a subset of the PDB200 benchmark set of nonhomologous structures representative of the PDB between 41 and 200 residues. For each protein, 14,000 decoys, previously generated with TASSER. were used. We selected a subset of 50 proteins for extended MD runs of 2 ns. In only 33% of the cases did the native trajectory snapshot have the lowest energy among decoys, and the average native-decoy energy gap was ¿22 kcal/mole. Moreover, the AMBER/GBSA energy does not generally exhibit a correlation with native-likeness as assessed by their RMSD from native, even when the relative weights of the AMBER/GBSA potential are optimized. Next, different versions of AMBER/GBSA force field will be tested and ways to improve the scoring abilities of the potential, based on decoy analysis, will be developed.by TASSER, were used. When the decoys were only locally minimized with AMBER/GBSA, nearly all of the native structures from the set are recognized as the lowest energy structures, with an average native-decoy energy gap of around 10% of the total native energy. The few failures involved proteins that were crystallized as a part of a complex. In a more difficult test, the decoys were subject to 100 ps Molecular Dynamics relaxation at 300¿ K followed by minimization. Now, the native structure is not the lowest energy one, and the AMBER/GBSA energy does not generally exhibit a correlation with native-likeness as assessed by the root-mean-square-deviation from native. In the coming year, the entire PDB200 set will be evaluated and an optimization of the AMBER/GBSA force field will be performed.