SIMULATING PROTEIN STRUCTURES, COMPLEXES, AND DYNAMICS

我们继续研究HIV-1包膜糖蛋白gp120的V3环。采用液态和固态核磁共振数据的实验约束，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程序中开发蒙特卡罗模拟技术，使用主链和侧链二面体构象的偏置搜索。软岩心电位计算和测试。评估了广义玻恩和有限差分泊松-玻尔兹曼溶剂化模型。我们继续对肺炎链球菌二氢叶酸还原酶（DHFR）的甲氧苄氨嘧啶耐药性进行计算研究。蒙特卡罗模拟了DHFR与抗生素甲氧苄啶结合的同源性模型。研究了il100突变为Leu或Met的结构效应。模拟表明，突变Ile100Leu导致主链松弛，破坏残基100和甲氧苄啶之间的氢键，从而对甲氧苄啶产生抗性。手稿正在准备中。以人醛脱氢酶（ALDH2）的晶体结构为基础，建立了扇贝中ω -结晶蛋白的同源性模型。通过实验和计算机模拟来探测该蛋白的功能。一篇论文正在印刷中。利用CHARMM模拟了底物3,4-二羟基苯基乙醇醛（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。我们特别指出了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联合势（GAMESS/CHARMM）来阐明5 -羟色胺n -乙酰转移酶的催化机制。

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).