Bayesian Statistics and Algorithms for Homology Modeling

描述（由申请人提供）：此更新申请扩展了前一个资助期的两个主题-用于结构测定和预测的蛋白质结构特征的现代统计分析，以及生物组装结构的分析和预测。它还将我们的工作扩展到一个新的领域-蛋白质晶体中生物相关相互作用的新观察的实验测试。在第一个目标中，我们追求 初步观察发现，蛋白质侧链的C β原子的位置随旋转异构体和骨架二面角φ和psi而变化。这种变化会影响结构测定和结构预测中整个侧链的位置。我们将进行一个新的回归分析的角度需要放置为每个chi 1旋转异构体作为一个函数的phi和psi与一个新的配方的基础上高斯过程回归。这些将被应用到侧链键角和二面角，以及骨干键角，我们已经调查了在以前的补助金期间。这些主链和侧链回归函数将被添加到我们的程序SCWRL 4和程序Rosetta中的侧链建模中。我们将进一步修改SCWRL 4进行预测的多个侧链的位置和它们的occupancy用于配体对接和药物设计，并允许纳入NMR实验的限制。我们的第二个主要目标是提高多个查询序列的生物组件的比较建模。这将涉及整个PDB的改进的家族和超家族分类，以及如何从蛋白质结构的不对称单元和晶体对称性推断生物组装的改进。我们将开发一个服务器，用于生物组件的自动建模，该服务器将提供基于可用模板的几个预测组件，并包括查询和模板结构的大量生物注释。在一个新的方向，我们将调查我们的观察同源二聚体相互作用的晶体激酶，可能是快照的反式自磷酸化事件。这些包括LCK和IGF 1 R的激活环交换二聚体，其可以是几乎所有人酪氨酸激酶的激活自磷酸化事件的模型。将利用几种实验方法，并将进行自磷酸化界面的进一步结构分析。

DESCRIPTION (provided by applicant): This renewal application expands upon two themes of the previous grant period - modern statistical analysis of protein structural features for use in structure determination and prediction, and the analysis and prediction of the structures of biological assemblies. It also extends our work into a new area - experimental tests of novel observations of biologically relevant interactions in protein crystals. In the first aim, we pursue preliminary observations that the position of the Cbeta atom of protein side chains varies with rotamer and with the backbone dihedrals phi and psi. This variation affects the position of the entire side chain in structure determination and structure prediction. We will perform a new regression analysis of the angles required to place Cbeta for each chi1 rotamer as a function of phi and psi with a novel formulation based on Gaussian process regression. These will be applied to side chain bond angles and dihedral angles as well as backbone bond angles we have investigated in the previous grant period. These backbone and side- chain regression functions will be added to modeling side chains in our program SCWRL4 and in the program Rosetta. We will further modify SCWRL4 to perform prediction of multiple side-chain positions and their occupancies for use in ligand docking and drug design and to allow the incorporation of NMR experimental constraints. Our second major aim is to improve the comparative modeling of biological assemblies for multiple query sequences. This will involve improved family and superfamily classifications of the entire PDB as well as improvements in how biological assemblies are inferred from asymmetric units and crystal symmetry of protein structures. We will develop a server for automated modeling of biological assemblies that will provide several predicted assemblies based on the available templates and include substantial biological annotations for the query and the template structures. In a new direction, we will investigate our observation of homodimer interactions in crystals of kinases that may be snapshots of trans- autophosphorylation events. These include the activation-loop swapped dimers of LCK and IGF1R that may be models of the activation autophosphorylation events for nearly all human tyrosine kinases. Several experimental approaches will be utilized and further structural analysis of the autophosphorylation interfaces will be performed.