MULTIRESOLUTION SAMPLING METHODS FOR PROTEIN & PEPTIDE CONFORMATIONAL SPACE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。该核心项目侧重于开发、验证和应用旨在探索蛋白质和肽折叠、配体对接和热力学方面的混合模型。AMBER99/GBSA电位识别能量最低的天然结构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基准集的一个子集，代表PDB在41到200个残基之间的非同源结构。对于每个蛋白质，14000个诱饵，以前用TASSER生成。被使用。我们选择了50个蛋白质子集进行2 ns的延长MD运行。在33%的情况下，天然轨迹快照的能量在诱饵中最低，平均能量差为¿22千卡/摩尔。此外，即使优化了AMBER/GBSA势的相对权重，AMBER/GBSA能量与原生相似度的RMSD评估也不存在相关性。接下来，将对不同版本的AMBER/GBSA力场进行测试，并在诱饵分析的基础上研究如何提高潜在的得分能力。使用了TASSER。当诱饵仅用AMBER/GBSA局部最小化时，几乎所有的天然结构都被识别为能量最低的结构，平均天然诱饵能量缺口约为总天然能量的10%。为数不多的失败涉及作为复合体一部分结晶的蛋白质。在一个更困难的测试中，诱饵在300 K时受到100 ps的分子动力学松弛，然后最小化。目前，原生结构并不是能量最低的结构，而且从与原生结构的均方根偏差来看，AMBER/GBSA能量与原生相似度的相关性并不普遍。在接下来的一年里，将对整个PDB200系统进行评估，并对AMBER/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.