MULTIRESOLUTION SAMPLING METHODS FOR PROTEIN & PEPTIDE CONFORMATIONAL SPACE

蛋白质多分辨率采样方法

• 批准号: 7358857
• 负责人: JEFFREY SKOLNICK
• 金额: $ 18.78万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7358857
• 关键词: MULTIRESOLUTION; SAMPLING; METHODS; PROTEIN; PEPTIDE

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。这个核心项目的重点是开发，验证和杂交模型的应用，旨在探索蛋白质和肽折叠，配体对接和热力学方面。在150种蛋白质上评估了AMBER 99/GBSA潜力识别天然结构的能力（能量最低）及其与天然相似性的相关性，这150种蛋白质是PDB 200基准组的一个子集，代表41至200个残基之间的PDB非同源结构。对于每种蛋白质，14，000个诱饵，之前用TASSER生成。用了我们选择了一个子集的50种蛋白质的扩展MD运行2 ns。只有33%的情况下，本机轨迹快照在诱饵中具有最低能量，平均本机诱饵能量差为£ 22大卡/摩尔。此外，AMBER/GBSA能量通常不表现出与天然相似性的相关性，如通过其来自天然的RMSD所评估的，即使当AMBER/GBSA势的相对权重被优化时。接下来，将测试不同版本的AMBER/GBSA力场，并使用基于诱饵分析的提高潜在得分能力的方法。developed.by当诱饵只局部最小化与AMBER/GBSA，几乎所有的天然结构从集合被认为是最低的能量结构，平均天然诱饵的能量差距约为总天然能量的10%。少数失败涉及作为复合物的一部分结晶的蛋白质。在一个更困难的测试中，诱饵在300 K下进行100 ps的分子动力学弛豫，然后最小化。现在，天然结构不是能量最低的结构，并且AMBER/GBSA能量通常不表现出与天然相似性的相关性，如通过与天然的均方根偏差所评估的。在未来的一年里，整个PDB 200系列将被评估，并将对AMBER/GBSA力场进行优化。