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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8320949
• 关键词: Accounting; Algorithms; Allosteric Regulation; Amino Acids; Base Sequence; Binding Sites; Biological Assay; Biological Process; Computer software; Coupled; Coupling; DNA; Distant; Engineering; Genetic Programming; Goals; Grant; Machine Learning; Measures; Methods; Modeling; Mutagenesis; NMR Spectroscopy; PDZ protein; Pattern; Physics; Play; Procedures; Property; Proteins; Protocols documentation; RNA Splicing; Research; Research Project Grants; Role; Scheme; Signal Transduction; Site; Solutions; Source Code; Specificity; System; Testing; Time; Work; base; comparative; design; fitness; model design; novel; novel strategies; practical application; protein folding; protein function; research study; simulation; success; transmission process; Accounting; Algorithms; Allosteric Regulation; Amino Acids; Base Sequence; Binding Sites; Biological Assay; Biological Process; Computer software; Coupled; Coupling; DNA; Distant; Engineering; Genetic Programming; Goals; Grant; Machine Learning; Measures; Methods; Modeling; Mutagenesis; NMR Spectroscopy; PDZ protein; Pattern; Physics; Play; Procedures; Property; Proteins; Protocols documentation; RNA Splicing; Research; Research Project Grants; Role; Scheme; Signal Transduction; Site; Solutions; Source Code; Specificity; System; Testing; Time; Work; base; comparative; design; fitness; model design; novel; novel strategies; practical application; protein folding; protein function; research study; simulation; success; transmission process

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）：在过去的10年中，在计算蛋白设计中取得了巨大进展。尽管大多数工作都集中在现有蛋白质的重新设计上，以增强其稳定性，特异性或新功能，但出现了新型蛋白质折叠的成功设计（不是自然发生）。但是，为了使蛋白质设计在实际应用中有用，在蛋白质 - 蛋白质和蛋白质DNA界面的设计中仍然存在许多挑战，以及蛋白质的动态特性等的设计，以克服这些挑战，一种实用的解决方案是开发更准确的得分功能。在实验和理论上都证明，在许多生物学过程中，遥远位点之间或遥远位点之间的内部和分子间信号传导在许多生物学过程中起着重要作用，例如信号传播和变构调节等。该R21授予的主要研究目标是将新算法和策略培养出新的算法和策略，以将新算法和策略融合到蛋白质的过程中。具体而言，在AIM 1中，我们建议使用基于序列的方法和基于物理学的方法研究蛋白质或蛋白质系统的位点耦合以及蛋白质或蛋白质系统的合作相互作用。将对现有方法进行批判性评估，并使用残留物相互作用能进行新的算法。在AIM 2中，将定制并集成到蛋白质设计的物理评分功能的位置耦合预测的最佳方法。为了确保这项研究赠款的成功，我们提出了四个方案，将站点耦合纳入蛋白质设计程序中。前两个方案代表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位点相关和物理评分功能的更高级集成。在最后一个协议中，我们建议开发一种新型方案和软件包，以使用残留物 - 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），基于一个假设，即相关信息在相互作用能量矩阵中本质上编码。该子AIM的成功将对理性蛋白质设计产生重大影响，因为它代表了位点位点耦合到物理评分功能的完美整合，并为进行蛋白质设计的新途径打开了新的途径。所有设计的有希望的PDZ蛋白将在折叠和功能测定中合成和测试。