SIMULATING PROTEIN STRUCTURES, COMPLEXES, AND DYNAMICS

我们对HIV-1包膜糖蛋白gp120的V3环进行了结构计算。采用了液态和固态核磁共振数据的实验约束，并使用CHARMM程序评估了不同的模拟退火方案。一篇论文已经发表，另一篇稿子即将提交发表。我们结束了与细胞周期蛋白依赖性激酶5结合的肽的研究。利用诱变实验和分子模型鉴定底物结合位点。结果发表了。我们继续在CHARMM程序中开发蒙特卡罗模拟技术，包括主链和侧链二面体构象的偏差搜索。采用广义玻恩的溶剂化自由能处理方法，对α螺旋的初步折叠模拟进行了验证。利用大肠杆菌中二氢叶酸还原酶的晶体结构建立了肺炎链球菌二氢叶酸还原酶（DHFR）的同源性模型。对抗生素甲氧苄啶结合的同源性模型进行了蒙特卡洛模拟。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。基于大肠杆菌亮氨酸/异亮氨酸/缬氨酸周质结合蛋白的晶体结构，建立了人钙受体（hCaR - ECD）胞外结构域的同源性模型。利用实验数据和模型推测了hCaR ECD的二聚体界面。一篇论文发表了。-分子建模，结构-功能关系，计算机模拟

We performed structure calculations for the V3 loop of the HIV-1 envelope glycoprotein gp120. Experimental restraints derived from liquid- and solid-state NMR data were used, and different simulated annealing protocols were evaluated using the CHARMM program. One paper has been published and another manuscript will soon be submitted for publication. We concluded our study of peptide binding to cyclin- dependent kinase 5. Mutagenesis experiments and molecular modeling were used to identify the substrate binding site. The results were published. We continued to develop Monte Carlo simulation techniques in the CHARMM program, incorporating biased searching of main-chain and side-chain dihedral conformations. The methods were tested with preliminary folding simulations of an alpha helix using a Generalized Born treatment of the solvation free energy. We made a homology model of dihydrofolate reductase (DHFR) from Streptococcus pneumonia from the crystal structure of DHFR from E. coli. Monte Carlo simulations were performed on the homology model 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 the extracellular domain of the human calcium receptor (hCaR ECD) based on the crystal structure of E. coli leucine/isoleucine/valine periplasmic binding protein. Experimental data and the model were used to infer the putative dimer interface of hCaR ECD. A paper has been published. - molecular modeling, structure-function relationship, computer simulation