Validation of biomacromolecular structures determined by NMR spectroscopy and deposited in the Protein Data Bank

通过核磁共振波谱法验证生物大分子结构并存入蛋白质数据库

• 批准号: BB/J007471/1
• 负责人: Gerard Kleywegt
• 金额: $ 39.21万
• 依托单位: European Bioinformatics Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ007471%2F1
• 关键词: Validation; biomacromolecular; structures; determined; NMR

The proposed research addresses the quality of 3D structures of important biological molecules such as proteins, nucleic acids and their complexes. Knowledge of these structures is essential in many areas of science and helps us understand the molecular basis of life and disease processes, design better drugs, improve the efficiency of enzymes used in the food, paper or agriculture industry, etc. Structural data is archived in a single, freely accessible, global archive called the Protein Data Bank (PDB). The structural information is deposited in the PDB by academic and industrial researchers from all over the world and is used by other scientists to advance our knowledge and understanding of human health, drug discovery, agriculture, etc. Every month, more than 25 million PDB structure files are downloaded from the websites of the four organisations that manage the PDB, the wwPDB consortium. Of more than 73000 entries in the PDB, about 86% were determined using a technique called X-ray crystallography, while 13% come from Nuclear Magnetic Resonance (NMR) spectroscopy.Structure determination by NMR typically involves weeks of data collection and manual analysis of complex spectra. As with any experimental technique, NMR structures may contain errors. To ensure that the data deposited in the PDB are reliable, there is a need for comprehensive validation, which tells both producers and users of structures how good (or bad) their structures are, both in absolute terms and compared to other structures. This helps NMR spectroscopists to produce better models, and structure users in academia or industry to better judge the quality of the data they want to use or to select the best data for their purposes. To address this issue, expert validation task forces (VTFs) have been set up by the wwPDB, which will recommend what validation methods should be used and which areas still require further research.Our aim is to improve validation of NMR-derived structures. The objectives of this proposal are:1. To implement the recommendations of the NMR VTF in an integrated software pipeline. This pipeline will be used to assess the quality of all NMR structures already in the PDB and of all structures that will be deposited in the future.2. To critically assess the utility, scope and limitations of current NMR validation tools. This will reveal why current validation methods sometimes fail, amongst other things.3. To develop new algorithms, procedures and tools for validation of NMR structures. Any limitations and weaknesses identified in the previous step will be addressed here.4. To disseminate validation-related information and newly developed validation methods for use by the wider scientific community. This ensures that NMR spectroscopists will be able to produce better models, and that non-expert users will be able to assess the quality of NMR structures available to them.One applicant, Prof. Kleywegt is head of the Protein Data Bank in Europe (PDBe). PDBe is a founding member of the wwPDB and is part of the European Bioinformatics Institute, a world leader in bioinformatics research and services. PDBe has extensive expertise in all major structure determination techniques and is already implementing the recommendations of the wwPDB X-ray VTF. The co-applicant , Prof. Vuister, is part of the Department of Biochemistry of the University of Leicester (UoL), home to 3 NMR- and 2 X-ray groups. He is a leading expert on validation of NMR-derived structures and is a member of the NMR VTF.

这项拟议的研究涉及蛋白质、核酸及其复合体等重要生物分子的3D结构的质量。对这些结构的了解在许多科学领域都是必不可少的，有助于我们了解生命和疾病过程的分子基础，设计更好的药物，提高食品、造纸或农业工业中使用的酶的效率等。结构数据保存在一个称为蛋白质数据库(PDB)的单一、可自由访问的全球档案中。结构信息由来自世界各地的学术和工业研究人员存储在PDB中，并被其他科学家用来增进我们对人类健康、药物发现、农业等的知识和理解。每月有超过2500万个PDB结构文件从管理PDB的四个组织的网站下载，即WWPDB联盟。在PDB的73000多个条目中，约86%是通过X射线结晶学技术确定的，13%来自核磁共振光谱分析。核磁共振结构确定通常需要数周的数据收集和对复杂光谱的手动分析。与任何实验技术一样，核磁共振结构可能包含错误。为了确保存放在PDB中的数据是可靠的，有必要进行全面验证，告诉结构的生产者和使用者其结构的绝对值和与其他结构相比的好坏。这有助于核磁共振光谱学家制作更好的模型，并帮助学术界或行业的用户更好地判断他们想要使用的数据的质量，或为他们的目的选择最佳数据。为了解决这个问题，WWPDB已经成立了专家验证任务小组(VTF)，他们将建议使用什么验证方法，以及哪些领域还需要进一步研究。我们的目标是改进核磁共振衍生结构的验证。这项提议的目标是：1.在一个综合软件流水线中实施核磁共振VTF的建议。这条管道将用于评估PDB中已经存在的所有核磁共振结构以及未来将沉积的所有结构的质量。严格评估当前核磁共振验证工具的实用性、范围和局限性。这将揭示为什么当前的验证方法有时会失败，以及其他事情。开发用于核磁共振结构验证的新算法、程序和工具。这里将讨论上一步中发现的任何限制和弱点。传播与验证相关的信息和新开发的验证方法，供更广泛的科学界使用。这将确保核磁共振光谱学家能够产生更好的模型，并且非专家用户将能够评估他们可用的核磁共振结构的质量。克利韦特教授是申请者之一，是欧洲蛋白质数据库(PDBe)的负责人。PDBe是WWPDB的创始成员之一，也是生物信息学研究和服务的世界领先者欧洲生物信息学研究所的一部分。PDBe在所有主要结构确定技术方面拥有广泛的专业知识，并已在实施WWPDB X射线VTF的建议。联合申请者Vuister教授是莱斯特大学(UOL)生物化学系的一部分，该系拥有3个核磁共振和2个X射线小组。他是核磁共振衍生结构验证方面的领先专家，也是核磁共振VTF的成员。

项目成果

Improving the representation of peptide-like inhibitor and antibiotic molecules in the Protein Data Bank.

• DOI: 10.1002/bip.22434
• 发表时间: 2014-06
• 期刊: BIOPOLYMERS
• 影响因子: 2.9
• 作者: Dutta, Shuchismita;Dimitropoulos, Dimitris;Feng, Zukang;Persikova, Irina;Sen, Sanchayita;Shao, Chenghua;Westbrook, John;Young, Jasmine;Zhuravleva, Marina A.;Kleywegt, Gerard J.;Berman, Helen M.
• 通讯作者: Berman, Helen M.

How community has shaped the Protein Data Bank.

• DOI: 10.1016/j.str.2013.07.010
• 发表时间: 2013-09-03
• 期刊: STRUCTURE
• 影响因子: 5.7
• 作者: Berman, Helen M.;Kleywegt, Gerard J.;Nakamura, Haruki;Markley, John L.
• 通讯作者: Markley, John L.

The Protein Data Bank archive as an open data resource.

• DOI: 10.1007/s10822-014-9770-y
• 发表时间: 2014-10
• 期刊: JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
• 影响因子: 3.5
• 作者: Berman, Helen M.;Kleywegt, Gerard J.;Nakamura, Haruki;Markley, John L.
• 通讯作者: Markley, John L.

The role of structural bioinformatics resources in the era of integrative structural biology.

• DOI: 10.1107/s0907444913001157
• 发表时间: 2013-05
• 期刊: Acta crystallographica. Section D, Biological crystallography
• 作者: Gutmanas A;Oldfield TJ;Patwardhan A;Sen S;Velankar S;Kleywegt GJ
• 通讯作者: Kleywegt GJ

Validation of Structures in the Protein Data Bank.

• DOI: 10.1016/j.str.2017.10.009
• 发表时间: 2017-12-05
• 期刊: Structure (London, England : 1993)
• 作者: Gore S;Sanz García E;Hendrickx PMS;Gutmanas A;Westbrook JD;Yang H;Feng Z;Baskaran K;Berrisford JM;Hudson BP;Ikegawa Y;Kobayashi N;Lawson CL;Mading S;Mak L;Mukhopadhyay A;Oldfield TJ;Patwardhan A;Peisach E;Sahni G;Sekharan MR;Sen S;Shao C;Smart OS;Ulrich EL;Yamashita R;Quesada M;Young JY;Nakamura H;Markley JL;Berman HM;Burley SK;Velankar S;Kleywegt GJ
• 通讯作者: Kleywegt GJ