III: Small: Graph Generative Deep Learning for Protein Structure Prediction

除了分子生物学之外，几十年的科学探索已经证明了基本形式是如何发挥作用的，无论是在理解统计物理中的相变，在网络科学中预测真实网络的演化和动力学，还是成功地将关节机器人手臂引导到目标姿势。所有这些科学领域的一个基本问题是，如何有效地探索动态系统的所有可能形式的空间，以揭示那些满足函数施加的非平凡约束的形式。在计算结构生物学中，这个问题最明显的实例是从头蛋白质结构预测(PSP)。PSP以结构驱动的观点来理解细胞中的分子机制，并试图通过了解蛋白质的化学组成来确定其一个或多个生物活性/天然结构。阐明这样的结构对于推断快速增长的编码蛋白质的基因序列的生物学活性，从而促进我们对细胞内部工作的理解是至关重要的。虽然PSP在随机优化下有一个自然的公式，但目前的努力正接近饱和点。这个项目提出了一种截然不同的互补方法。受生成性深度学习最近势头的启发，该项目在生成性、对抗性深度学习的保护伞下进行从头开始的PSP。该方法牢固地植根于信息集成和信息学，因为它提出了在对抗性环境中学习的生成模型，以生成类似于本地的三级蛋白质结构。该项目使机器学习、深度学习和信息集成的研究人员受益，他们对图形生成模型、分子生成和蛋白质结构预测感兴趣。该项目将导致开放源代码、在线教学模块和教程、公开可用的数据和模型、研讨会、软件演示，并将扩大未被充分代表的学生参与计算的范围。该项目的活动在信息集成和信息学的保护伞下绘制了一条新的算法路径，以解决目前分子生物学中与结构功能相关的问题的僵局。重点研究了从头蛋白质结构预测问题。由于实验结构确定落后于高通量测序技术快速增长的蛋白质编码基因序列数量，计算方法在分子生物学研究中发挥着核心作用。随机优化已经取得了很大的进展，但目前的方法正在经历回报递减，部分原因是复杂搜索空间中的资源感知勘探-开采控制和内在不准确的评分函数方面的根本挑战。该项目提出了一种在生成性、对抗性深度学习的保护伞下进行结构预测的新方法，利用了图形生成性学习、对抗性学习和深度学习方面的最新进展和机会。生成模型在对抗性环境中学习，以生成类似于本地的三级蛋白质结构。拟议的活动跨越多个学科，有望在机器学习、深度学习、可解释人工智能、分子建模和计算生物学方面做出普遍贡献。这项工作还将使对复杂、动态系统建模感兴趣的研究人员和学生受益。调查人员将通过C++和Python语言的开源代码传播拟议的研究，以便接触到不同的研究人员和学生社区、在线教学模块和教程、经培训的模型和数据。他们将通过研讨会、教程和软件演示积极教育相关社区。这个跨学科的项目也创造了极好的机会来扩大所有背景的代表不足的学生在计算方面的参与。这个奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Decades of scientific enquiry beyond molecular biology have demonstrated just how fundamental form is to function, whether in understanding phase transitions in statistical physics, predicting the evolution and dynamics of real networks in network science, or successfully steering an articulated robot arm to a target pose. A fundamental question in all these scientific domains is how to effectively explore the space of all possible forms of a dynamic system to uncover those that satisfy non-trivial constraints imposed by function. The most visible instantiation of this question in computational structural biology is de-novo protein structure prediction (PSP). PSP takes a structure-driven view of understanding molecular mechanisms in the cell and seeks to determine one or more biologically-active/native structures of a protein from knowledge of its chemical composition. Elucidating such structures is central to inferring the biological activities of a rapidly-growing number of protein-encoding gene sequences and thus advancing our understanding of the inner workings of a cell. While PSP has a natural formulation under stochastic optimization, current efforts are approaching a saturation point. This project proposes a radically-different, complementary approach. Inspired by recent momentum in generative deep learning, the project approaches de-novo PSP under the umbrella of generative, adversarial deep learning. The approach is firmly grounded in information integration and informatics, as it proposes generative models that learn in an adversarial setting to generate native-like tertiary protein structures. The project benefits researchers in machine learning, deep learning, and information integration with interests in graph generative models, molecule generation, and protein structure prediction. The project will result in open-source codes, online teaching modules and tutorials, publicly-available data and models, workshops, software demos, and will broaden the participation in computing of under-represented students.The activities in this project chart a new algorithmic path under the umbrella of information integration and informatics to address the current impasse in structure-function related problems in molecular biology. The focus is on the de-novo protein structure prediction problem. With experimental structure determination lagging behind the rapidly-growing number of protein-encoding gene sequences by high-throughput sequencing technologies, computational approaches have a central role in molecular biology research. Great progress has been made through stochastic optimization, but current approaches are experiencing diminishing returns, partly due to fundamental challenges concerning the resource-aware exploration-exploitation control in complex search spaces and inherently inaccurate scoring functions. This project puts forth a novel approach to structure prediction under the umbrella of generative, adversarial deep learning, leveraging recent advances and opportunities in graph generative learning, adversarial learning, and deep learning. Generative models learn in an adversarial setting to generate native-like tertiary protein structures. The proposed activities span multiple disciplines and promise to make general contributions in machine learning, deep learning, explainable AI, molecular modeling, and computational biology. The work will also benefit researchers and students interested in modeling complex, dynamic systems. The investigators will disseminate the proposed research via open-source codes in C++ and Python so as to reach diverse communities of researchers and students, online teaching modules and tutorials, trained models and data. They will actively educate involved communities through workshops, tutorials, and software demonstrations. This interdisciplinary project also creates excellent opportunities to broaden the participation in computing of under-represented students of all backgrounds.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.