Collaborative Research: CIBR: Incorporating Crystallography and Cryo-EM Tools in Foldit

结构生物学家的目标是在原子分辨率上可视化生物分子，这是理解生物学的各个方面，包括疾病及其治疗的关键一步。用于结构测定的主要实验方法，称为冷冻电子显微镜和x射线晶体学，依赖于将生物分子中的原子装配到三维“地图”中，寻求与实验数据的一致性。这个拟合过程既费力又困难，但初步研究表明，通过玩生物化学电脑游戏Foldit，公民科学家可以非常有效地完成这项任务。作为一个重要的公民科学电脑游戏，Foldit自推出以来已经有超过60万人玩。该项目旨在提高Foldit的能力，使科学家和公民科学家能够准确地构建不同类型和大小的生物结构。这种能力可以极大地提高科学理解许多生物现象基础的能力。除了这些科学效益外，该项目还有利于科学教育和整个社会。这项新功能将提高使用Foldit的教育选择的多样性和质量，使其成为科学界与社会之间的主要接口。有一个持续的需要改进的方法来解决晶体和低温电镜结构。Foldit是一个公民科学项目，在这个项目中，用户可以帮助解决许多生物化学问题，包括蛋白质结构解决项目中的模型构建和真实空间细化。早期的测试表明，这些企业可以生产出高质量的晶体和低温电镜结构，但要使Foldit成为解决结构问题的首选，还需要进行许多改进。最近，除了标准的公民科学Foldit谜题外，还推出了新的Foldit版本，可供单个科学家或实验室小组使用。这些选项将被用来为结构生物学问题创建一个多尺度建模工具箱。本授权中提出的补充内容包括在Foldit中集成新的晶体学改进功能，并添加新的模式，允许在Foldit中处理更大的蛋白质进行冷冻电镜。总之，这些改进将使Foldit成为最先进的晶体学和低温电镜结构求解套件。项目成果的重大更新可在https://www.fold.it.This上找到，该奖项反映了美国国家科学基金会的法定使命，并通过基金会的智力价值和更广泛的影响审查标准进行评估，认为值得支持。

The goal of structural biologists is to visualize biomolecules at atomic resolution, which is a critical step in understanding all aspects of biology, including diseases and their cures. The dominant experimental methods for structure determination, called Cryo-Electron Microscopy and X-Ray Crystallography, rely upon fitting the atoms from biological molecules into three-dimensional “maps”, seeking agreement with experimental data. This fitting process is laborious and difficult, but preliminary studies have shown that this task could be performed very effectively by citizen scientists playing the biochemistry computer game Foldit. As a premier citizen science computer game, Foldit has already been played by over 600,000 people since its inception. This project aims to improve the capabilities of Foldit to enable scientists and citizen scientists alike to accurately build biological structures of varying types and sizes. This capability could strongly improve science’s ability to understand the basis of many biological phenomena. In addition to these scientific benefits, this project benefits both science education and society as a whole. This new capability will enhance the variety and quality of educational options using Foldit, improving it as a major interface between the scientific community and society.There is an ongoing need for improvements for methods to solve crystal and cryo-EM structures. Foldit is a citizen science project in which users aid in many biochemistry problems, including model building and real space refinement in protein structure solving projects. Early tests suggest that these ventures produce high quality crystal and cryo-EM structures, but many improvements are needed to make Foldit a go-to option for structure solving problems. Recently, new versions of Foldit have been introduced that can be used by single scientists or lab groups, in addition to standard citizen science Foldit puzzles. These options will be leveraged to create a multi-scale modeling toolbox for structural biology problems. The additions proposed in this grant include integrating new crystallography refinement capabilities within Foldit, and adding new modes that allow much larger proteins to be handled in Foldit for cryo-EM. Together, these improvements will make Foldit a state-of-the-art structure solving suite for crystallography and cryo-EM. Significant updates in the results of the project can be found at https://www.fold.it.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.