SIMULATING PROTEIN STRUCTURES, COMPLEXES, AND DYNAMICS

模拟蛋白质结构、复合物和动力学

• 批准号: 6431908
• 负责人: PETER J STEINBACH
• 金额: --
• 依托单位: CENTER FOR INFORMATION TECHNOLOGY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431908
• 关键词: bioenergetics; computer simulation; conformation; molecular dynamics; myoglobin; nuclear magnetic resonance spectroscopy; physical model; protein kinase; protein structure; site directed mutagenesis

We continued our study of the V3 loop of the HIV-1 envelope glycoprotein gp120. Experimental restraints derived from liquid- and solid-state NMR data were used, and simulated annealing was performed using the XPLOR program. We published a second paper. We continued to develop Monte Carlo simulation techniques in the CHARMM program, using biased searching of main-chain and side-chain dihedral conformations. Soft-core potentials were implemented and tested. Generalized Born and finite-difference Poisson-Boltzmann solvation models were evaluated. We continued our computational study of trimethoprim resistance in dihydrofolate reductase (DHFR) from Streptococcus pneumonia. Monte Carlo simulations were performed on a homology model of DHFR with the antibiotic trimethoprim bound. The structural effects of mutating Ile 100 to Leu or Met were investigated. Simulations suggested that the mutation Ile100Leu results in main-chain relaxation that breaks a hydrogen bond between residue 100 and trimethoprim and thus confers resistance to trimethoprim. A manuscript is in preparation. We made a homology model of an omega-crystallin from scallop, based on the crystal structure of human aldehyde dehydrogenase (ALDH2). Experiments and computer modeling were used to probe the function of this protein. A paper is in press. We modeled the binding mode of substrate 3,4-dihydroxyphenylglycolaldehyde (DHMAL) and its derivatives at the active site of aldose reductase utilizing CHARMM. This modeling provided a structural basis for the reduction of DHMAL by aldose reductase. In particular, we pointed out the importance of the 2'-hydroxl group of DHMAL during catalysis. A manuscript is in preparation. We are in the process of elucidating the catalytic mechanism of Serotonin N-acetyltransferase utilizing combined potentials of quantum mechanics and molecular mechanics (GAMESS/CHARMM).

我们继续研究HIV-1包膜糖蛋白gp 120的V3环。 来自液体和固体状态的NMR数据的实验约束，并使用XPLOR程序进行模拟退火。 我们发表了第二篇论文。我们继续在CHARMM程序中开发Monte Carlo模拟技术，使用主链和侧链二面角构象的偏置搜索。 软核潜力的实施和测试。 广义玻恩和有限差分Poisson-Boltzmann溶剂化模型进行了评估。我们继续我们的计算研究甲氧苄啶耐药性的二氢叶酸还原酶（DHFR）肺炎链球菌。在具有抗生素甲氧苄啶结合的DHFR的同源性模型上进行Monte Carlo模拟。 研究了Ile 100突变为Leu或Met的结构效应。模拟表明，突变Ile 100 Leu导致主链松弛，破坏残基100和甲氧苄啶之间的氢键，从而赋予耐药性甲氧苄啶。手稿正在准备中。根据人乙醛脱氢酶（ALDH 2）的晶体结构，建立了扇贝ω-晶体蛋白的同源模型。 实验和计算机模拟被用来探测这种蛋白质的功能。 一篇论文正在印刷中.我们利用CHARMM模拟了底物3，4-二羟基苯乙醇醛（DHMAL）及其衍生物在醛糖还原酶活性位点的结合模式。 该模型为醛糖还原酶还原DHMAL提供了结构基础。特别指出了DHMAL的2 ′-羟基在催化过程中的重要性。手稿正在准备中。我们正在利用量子力学和分子力学的结合势（GAMESS/CHARMM）阐明5-羟色胺N-乙酰转移酶的催化机制。