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。来自液体和固体核磁共振数据的实验约束，并使用CHARMM程序进行了评估，不同的模拟退火协议。一份论文已经发表，另一份手稿不久将提交出版。我们结束了我们的研究肽结合细胞周期蛋白依赖性激酶5。突变实验和分子模拟用于确定底物结合位点。研究结果已经公布。我们继续在CHARMM程序中开发Monte Carlo模拟技术，将主链和侧链二面角构象的有偏搜索结合起来。初步折叠模拟的α螺旋使用广义玻恩治疗的溶剂化自由能的方法进行了测试。根据肺炎链球菌二氢叶酸还原酶（DHFR）的晶体结构，建立了DHFR的同源模型。杆菌在抗生素甲氧苄啶结合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Ile100Leu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。根据E.大肠杆菌亮氨酸/异亮氨酸/缬氨酸周质结合蛋白。实验数据和模型被用来推断推定的二聚体界面的hCaR ECD。发表了一篇论文。- 分子模拟，构效关系，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