Protein Design Using Physical Scoring Functions integrated with Site Couplings

使用与位点耦合集成的物理评分函数进行蛋白质设计

基本信息

批准号：
8320949
负责人：
Junmei Wang
金额：
$ 19.88万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Tremendous progress has been made in computational protein design in the last 10 years. Though most work has focused on redesign of existing proteins to enhance their stability, specificity or new functionality, successful designs of novel protein folds (not naturally occurring) have emerged. However, to make protein design useful in practical applications, many challenges still exist in the design of protein-protein and protein- DNA interface and the design of dynamic properties of proteins, etc. To conquer those challenges, a practical solution is to develop more accurate scoring functions. It has been proved both experimentally and theoretically that intra and intermolecular signaling between distant sites within one or among many proteins plays a significant role in many biological processes, such as signal transmission and allosteric regulation, etc. The main research goal of this R21 grant is to develop new algorithms and strategies to incorporate the site-site couplings into a protein design procedure. Specifically, in Aim 1, we propose to study the site-site couplings and cooperative interactions of a protein or protein system using both the sequence-based and the physics-based approaches. Critical assessment of the existing approaches will be conducted and a novel algorithm will be developed using the residue-residue interaction energies. In Aim 2, the best methods for site-site couplings prediction will be tailored and integrated to physical scoring functions of protein design. To guarantee the success of this research grant, we propose four schemes to incorporate/combine the site-site coupling into a protein design procedure. The first two schemes represent simple combinations of sequence-based and physics-based protein design approaches; on the other hand, the next two schemes represent a more advanced integration of site-site correlations and physical scoring functions. In the last protocol, we propose to develop a novel scheme and software package to conduct protein design using the residue-residue interaction energies as a template. This approach, which is referred to as correlation embedding (CE), is based on a hypothesis that the correlation information is intrinsically encoded in the interaction energy matrix. The success of this sub-aim will have a great impact on rational protein design, as it represents a perfect integration of site-site couplings into a physical scoring function and opens a new avenue to conduct protein design. All the designed promising PDZ proteins will be synthesized and tested in both folding and functional assays.

描述（由申请人提供）：过去 10 年，计算蛋白质设计取得了巨大进展。尽管大多数工作都集中在重新设计现有蛋白质以增强其稳定性、特异性或新功能，但新型蛋白质折叠（非自然发生）的成功设计已经出现。然而，为了使蛋白质设计在实际应用中发挥作用，蛋白质-蛋白质、蛋白质-DNA界面的设计以及蛋白质动态特性的设计等方面仍然存在许多挑战。为了克服这些挑战，实际的解决方案是开发更多准确的评分功能。实验和理论上都证明，一种或多种蛋白质之间的远距离位点之间的分子内和分子间信号传导在许多生物过程中发挥着重要作用，例如信号传递和变构调节等。本次R21资助的主要研究目标是开发新的算法和策略，将位点耦合纳入蛋白质设计程序。具体来说，在目标 1 中，我们建议使用基于序列和基于物理的方法来研究蛋白质或蛋白质系统的位点耦合和协作相互作用。将对现有方法进行严格评估，并利用残基-残基相互作用能量开发一种新算法。在目标 2 中，位点耦合预测的最佳方法将被定制并集成到蛋白质设计的物理评分函数中。为了保证这项研究资助的成功，我们提出了四种方案，将位点耦合纳入蛋白质设计程序。前两个方案代表了基于序列和基于物理的蛋白质设计方法的简单组合；另一方面，接下来的两个方案代表了站点间相关性和物理评分功能的更高级的集成。在最后一个协议中，我们建议开发一种新的方案和软件包，以残基-残基相互作用能作为模板进行蛋白质设计。这种方法称为相关嵌入（CE），基于相关信息本质上编码在交互能量矩阵中的假设。该子目标的成功将对合理的蛋白质设计产生巨大影响，因为它代表了位点耦合与物理评分函数的完美整合，并为进行蛋白质设计开辟了新途径。所有设计的有前景的 PDZ 蛋白都将在折叠和功能测定中合成和测试。