Proteins are dynamic macromolecules. Knowledge of a protein's thermally accessible conformations is critical to determining important transitions and designing therapeutics. Accessible conformations are highly constrained by a protein's structure such that concerted structural changes due to external perturbations likely track intrinsic conformational transitions. These transitions can be thought of as paths through a conformational landscape. Crystallographic drug fragment screens are high-throughput perturbation experiments, in which thousands of crystals of a drug target are soaked with small-molecule drug precursors (fragments) and examined for fragment binding, mapping potential drug binding sites on the target protein. Here, we describe an open-source Python package, COnformational LAndscape Visualization (COLAV), to infer conformational landscapes from such large-scale crystallographic perturbation studies. We apply COLAV to drug fragment screens of two medically important systems: protein tyrosine phosphatase 1B (PTP1B), which regulates insulin signaling, and the SARS CoV-2 Main Protease (MPro). With enough fragment-bound structures, we find that such drug screens enable detailed mapping of proteins' conformational landscapes.

Ammaar A. Saeed

Margaret A. Klureza

Doeke R. Hekstra

Journal of Chemical Information and Modeling

JOURNAL OF CHEMICAL INFORMATION AND MODELING 发表论文报告化学信息学和分子建模领域的新方法和/或重要应用。具体主题包括化学数据库的表示和基于计算机的搜索、分子建模、新材料、催化剂或配体的计算机辅助分子设计、化学软件的新计算方法或有效算法的开发，以及包括生物分析在内的生物制药化学活动和其他与药物发现相关的问题。精明的化学家、计算机科学家和信息专家关注本月的富有洞察力的研究、编程创新和软件评论，以跟上这个完整的、多学科领域的进步。作为订阅者，您将了解数据库搜索系统、图论在化学问题中的应用、子结构搜索系统、模式识别和聚类、化学和物理数据分析、分子建模、图形和自然语言界面、文献计量和引文分析以及综合设计和反应数据库。

The Journal of Chemical Information and Modeling publishes papers that report new methods and significant applications in the fields of cheminformatics and molecular modeling. Specific topics include the representation of chemical databases and computer-based searches, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, the development of new computational methods or efficient algorithms for chemical software, as well as research related to biopharmaceutical chemistry activities and other drug discovery issues. This journal attracts chemists, computer scientists, and information specialists who are interested in insightful research, programming innovations, and software reviews to keep up with advancements in this comprehensive, multidisciplinary field. As a subscriber, you will learn about database search systems, the application of graph theory to chemical problems, substructure search systems, pattern recognition and clustering, chemical and physical data analysis, molecular modeling, graphical and natural language interfaces, bibliometrics and citation analysis, as well as integrated design and reaction databases.

《Journal of Chemical Information and Modeling》发表关于化学信息学和分子建模领域的新方法和重要应用的论文。具体主题包括化学数据库的表示与计算机搜索、分子建模、新材料、催化剂或配体的计算机辅助分子设计、化学软件的新计算方法或有效算法的开发，以及生物制药化学活动和药物发现相关问题的研究。该期刊吸引了化学家、计算机科学家和信息专家关注本月的研究成果、编程创新和软件评测，以跟上这一多学科领域的进展。作为订阅者，您将了解数据库搜索系统、图论在化学问题中的应用、子结构搜索系统、模式识别与聚类、化学和物理数据分析、分子建模、图形和自然语言界面、文献计量与引文分析，以及综合设计与反应数据库等内容。

Category	Quartile
化学	2
化学, 药物化学	2
化学, 化学综合	2
化学, 计算机信息系统	3
化学, 计算机跨学科应用	3

Mapping Protein Conformational Landscapes from Crystallographic Drug Fragment Screens

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Journal Info

Category	Quartile
COMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS	1