SIMULATING PROTEIN STRUCTURES, COMPLEXES, AND DYNAMICS

我们使用了同源建模和蒙特卡罗方法 (MC)结合协作者的绑定亲和力进行模拟 预测分子间重要接触的实验 10个残基的多肽与细胞周期蛋白依赖性激酶5的对接 (CDK5)。Cdk5的结构模型是基于已知的 同源蛋白CDK2的结构。执行MC运行 其中多肽底物被引导到特定的蛋白质 实验建议的残留物。反过来，建模的结果 被用来建议定点突变和结合 实验/理论尝试中的分析以模拟 CDK5-多肽复合体。一份手稿被提交给 出版。我们还在 CHARMM程序的势能函数 用计算机固体核磁共振观察Phi-psi构象 模拟。由固态获得的局部结构信息 核磁共振和CHARMM力场一起被用来 研究HIV-1 V3环的不同构象 Gp120蛋白。提交了一份手稿供出版。我们 探讨了蛋白质突变的结构后果 泛素C末端水解酶L1。这种突变一直是 在一个患有帕金森氏症的家庭中被确认。我们表演了 天然和突变体的多重分子动力学模拟 用于评估平均结构和原子差异的蛋白质 波动。一份手稿已于#年接受出版。 自然。我们继续研究模拟结构的依赖性 和动态的环境考虑因素，如溶剂化。 我们正在模拟肌红蛋白和其他各种蛋白质 环境(水合蛋白质、溶液中的蛋白质、 水晶)。不同温度下的动态模拟 基本生物物理兴趣的问题和帮助表征 不同的模拟方法。

We have used homology modeling and Monte Carlo (MC) simulation in concert with collaborators' binding-affinity experiments to predict the important intermolecular contacts in the docking of a 10-residue peptide to cyclin dependent kinase 5 (cdk5). A structural model of cdk5 was based on the known structure of a homologous protein, cdk2. MC runs were performed in which the peptide substrate was guided toward specific protein residues suggested by experiments. In turn, results of the modeling were used to suggest site-directed mutations followed by binding assays in an experimental/theoretical attempt to model the cdk5-peptide complex. A manuscript was submitted for publication.We have also introduced a novel empirical term in the potential energy function of the CHARMM program to favor phi-psi conformations observed by solid-state NMR in computer simulations. The local structural information obtained by solid-state NMR, along with the CHARMM force field, was used to investigate alternative conformations of the V3 loop of the HIV-1 gp120 protein. A manuscript was submitted for publication.We probed the structural consequences of a mutation in the protein ubiquitin C-terminal-hydrolase L1. This mutation has been identified in a family with Parkinson's disease. We performed multiple molecular dynamics simulations of the native and mutant proteins to assess differences in average structure and atomic fluctuation. A manuscript has been accepted for publication in Nature.We continue to study the dependence of simulated structure and dynamics on environmental considerations such as solvation. We are simulating myoglobin and other proteins in various environments (hydrated protein, protein in solution, protein in crystal). Simulations of dynamics at various temperatures address questions of basic biophysical interest and help characterize different simulation approaches.