Nonlinear dimensionality reduction and enhanced sampling in molecular simulation using auto-associative neural networks

伊利诺伊大学厄巴纳-香槟分校的Andrew Ferguson获得了化学系化学理论，模型和计算方法项目的奖项，以建立新的理论方法和计算工具来加速蛋白质折叠的分子模拟。该项目由材料研究部的凝聚态物质和材料理论计划共同资助。蛋白质是执行生命基本功能的分子工具。 蛋白质已经进化成能够完成这些任务的形状。确定蛋白质的形状和运动可以帮助揭示它是如何工作的，并为如何设计新的蛋白质以帮助治疗疾病、生产生物燃料或制造新材料提供信息。蛋白质的计算机模拟非常有用，因为它们可以识别所有组成原子的精确位置和运动。然而，对于除了最小的蛋白质之外的所有蛋白质，即使使用强大的超级计算机也无法准确预测它们的结构和运动。加速这些模拟的方法已经被开发出来，但是要想很好地工作，他们需要对蛋白质将进行的结构重排进行很好的估计。这是一个问题，因为这通常是模拟试图回答的问题。在这项工作中，Ferguson教授正在开发一种新的方法来加速蛋白质折叠模拟，这种方法使用一种称为人工神经网络的机器学习，因为它们基于大脑中神经元的结构。 神经网络允许计算机确定这些重要的结构路径，并使用它们来使模拟运行得更快。这种新方法正被用于帮助了解与癌症和艾滋病毒感染有关的大蛋白质。 它也被纳入流行的模拟软件，可供公众免费下载。弗格森教授正在为本科生提供研究机会，与他一起在这个项目上工作，他正在开发计算材料科学的实践研讨会，作为伊利诺伊大学女孩学习材料（GLAM）夏令营的一部分。这项工作的目的是建立一个非线性的机器学习方法来发现集体变量的蛋白质折叠，并使用这些变量来执行增强采样的分子动力学模拟。增强采样技术在加速构象采样中的成功是基于与重要分子运动相关的良好集体变量（CV）的可用性。现有的非线性降维技术（例如，扩散映射、Isomap、局部线性嵌入）可以巧妙地发现好的CV，但不能提供显式坐标映射，因此必须在代理变量中低效地间接进行有偏采样。这项工作建立了一个新的增强的采样方法的基础上，自动联想人工神经网络（“自动编码器”），发现CV是明确的可微函数的原子坐标，并允许计算分析偏置力。这种方法被称为梅萨（自动编码分子增强采样）。梅萨在短肽丙氨酸二肽和Dahan-cage上进行了验证，并用于发现在许多癌症中过表达的激酶和HIV表面上存在的包膜蛋白的亚稳态和结构转变。梅萨通过与OpenMM和PLUMED的开发人员合作，为这些软件包的未来版本提供方法，从而广泛地提供给分子模拟社区。积极的研究经验对本科生的成功和保留有很大的好处，这项工作支持在每年的奖项10周的夏季研究机会。弗格森教授还开发了新的和令人兴奋的内容非常成功的女孩学习材料（GLAM）在伊利诺伊大学夏令营说明和促进计算材料科学女高中生和提高女性入学率在干学位课程。

Andrew Ferguson of the University of Illinois at Urbana-Champaign is supported by an award from the Chemical Theory, Models and Computational Methods Program in the Chemistry Division to establish new theoretical approaches and computational tools to accelerate molecular simulations of protein folding. This project is cofunded by the Condensed Matter and Materials Theory Program in the Division of Materials Research. Proteins are molecular workhorses that perform the essential functions of life. Proteins have evolved to adopt shapes that enable them to do these tasks. Determining the shape and motions of a protein can help reveal how it works and inform how to design new proteins to help treat disease, produce biofuels, or make new materials. Computer simulations of proteins are very useful in that they can identify the precise locations and motions of all the constituent atoms. For all but the smallest proteins, however, it is too computationally intensive to accurately predict their structure and motions even with powerful supercomputers. Ways to accelerate these simulations have been developed, but to work well they need good estimates of the structural rearrangements that the protein will make. This is a problem, since this is usually the question the simulations are trying to answer. In this work, Professor Ferguson is developing a new approach to accelerate protein folding simulations using a type of machine learning known as artificial neural networks so-called because they are based on the structure of neurons in the brain. Neural networks allow computers to both determine these important structural pathways and use them to make simulations run faster. This new approach is being used to help understand large proteins involved in cancer and HIV infection. It is also being incorporated into popular simulation software available for free public download. Professor Ferguson is providing research opportunities for undergraduates to work with him on this project and he is developing hands-on workshops in computational materials science as part of the Girls Learning About Materials (GLAM) summer camp at the University of Illinois. The aim of this work is to establish a nonlinear machine learning approach to discover collective variables for protein folding and to use these variables to perform enhanced sampling in molecular dynamics simulations. The success of enhanced sampling techniques in accelerating conformational sampling is predicated on the availability of good collective variables (CVs) correlated with important molecular motions. Existing nonlinear dimensionality reduction techniques (e.g., diffusion maps, Isomap, land ocally linear embedding) can ably discover good CVs, but do not furnish the explicit coordinate mapping so that biased sampling must be conducted inefficiently and indirectly in proxy variables. This work establishes a new enhanced sampling approach based on auto-associative artificial neural networks ("autoencoders") to discover CVs that are explicit differentiable functions of the atomic coordinates and to permit calculation of analytical biasing forces. This approach is termed MESA (Molecular Enhanced Sampling with Autoencoders). MESA is validated on the short peptides alanine dipeptide and tryptophan-cage, and deployed to discover metastable states and structural transitions in a kinase overexpressed in many cancers and an envelope protein presented on the surface of HIV. MESA is made broadly available to the molecular simulation community by collaborating with the developers of OpenMM and PLUMED to contribute the approach to future releases of these software packages. Positive research experiences have great benefits for undergraduate success and retention and this work supports 10-week summer research opportunities during each year of the award. Professor Ferguson is also developing new and exciting content for the highly successful Girls Learning About Materials (GLAM) summer camp at the University of Illinois to illustrate and promote computational materials science among female high school students and elevate female enrollment in STEM degree programs.