Revealing pathways and kinetics of molecular recognition with advanced molecular simulation algorithms

项目摘要 纳米生物学是由分子识别驱动的。细胞内排列着受体， 无数的生物分子并将信号传递到细胞内部。这构成了细胞间通讯的基础 使多细胞生物得以繁衍对分子识别的理解 对人类健康很重要，因为它是我们免疫系统对病毒，细菌和 癌细胞不幸的是，这些识别过程通常比规范的识别过程复杂得多。 “锁和钥匙”模式。许多神经肽和肽激素的长度是几十个残基， 显示出巨大的结构可塑性。在这种动力学系统中研究分子识别是一个重要的课题。 这是一个挑战，因为仅从结构方法中只能收集到对相互作用的有限理解。 计算分子动力学（MD）模拟使我们能够查看复杂的生物分子系统， 原子细节，使我们能够计算结合和解结合率，并研究其分子决定因素。一 MD的一个众所周知的缺点是探索构象景观而不陷入困境的困难 局部自由能极小值PI（Dickson）拥有十多年开发新方法的经验， 解决这个问题，能够计算复杂系统中的转换率。特别是REVO 方法（“通过变异优化重新加权集合”）已经在解结合途径上显示出成功， 药物样配体的平均首次通过时间长达34分钟，这是典型药物的数十亿倍。 直接MD的范围。这是在不向系统施加偏置力或不进行任何操作的情况下完成的。 关于平衡条件的假设。REVO本质上是轨迹空间中的进化算法， 其中一大组轨迹并行运行，并且使用 测量与其他全体成员的距离。这些离群值被“克隆”，这增加了 看到长时间尺度事件发生的概率，即使是在短时间的轨迹。 拟议的工作将增加这种方法的最新进展，自动检测缓慢 集体变量（或“CV”）。VAMPnet（“马尔可夫过程的变分方法”）方法将 用于检测要在REVO距离计算中使用的CV组。一种用于迭代地改进 还提出了速率计算的准确性（“异步加权系综”）。综合这些 这些发展将成为研究复杂生物分子中长时间尺度事件的有力工具。 这些系统将免费提供给其他研究人员。通过与实验性 合作伙伴，这种方法将被应用于揭示分子机制：i）肽信号传导的B类 GPCR（Aim 2），和ii）通过噬菌体尾刺蛋白特异性识别细菌LPS（Aim 3）。这些 这些机制将为具有潜在治疗应用的新分子的设计提供信息。

Project Summary Biology at the nanoscale is driven by molecular recognition. Cells are lined with receptors that recognize a myriad of biomolecules and transmit signals to the cell interior. This forms the basis of cell-cell communication that allows multicellular organisms to thrive. An understanding of molecular recognition is tremendously important for human health, as it underlies our immune system’s response to threats from viruses, bacteria and cancer cells. Unfortunately, these recognition processes are often much more complicated than the canonical “lock-and-key” paradigm. Many neuropeptides and peptide hormones are dozens of residues in length and can exhibit tremendous structural plasticity. The study of molecular recognition in such dynamic systems is a challenge, as only a limited understanding of the interactions can be gleaned from structural approaches alone. Computational molecular dynamics (MD) simulation allows us to view complex biomolecular systems in atomic detail, allowing us to compute binding and unbinding rates, and to study their molecular determinants. A well-known drawback of MD is the difficulty of exploring conformational landscapes without getting trapped in local free energy minima. The PI (Dickson) has over a decade of experience developing new methods for tackling this problem, which are able to calculate transition rates in complex systems. Particularly, the REVO method (“Reweighting Ensembles by Variation Optimization”) has shown success on unbinding pathways of drug-like ligands with mean first passage times up to 34 minutes, which is billions of times beyond the typical reach of straightforward MD. This is done without applying biasing forces to the system or making any assumptions about equilibrium conditions. REVO is essentially an evolutionary algorithm in trajectory space, where a large group of trajectories are run in parallel, and outlier trajectories are identified using a measurement of distance to other ensemble members. These outliers are “cloned”, which increases the probability of seeing long-timescale events happen, even in short-time trajectories. The proposed work will augment this method with recent advances in the automatic detection of slow collective variables (or “CVs”). The VAMPnet (“Variational Approach for Markov Processes”) approach will be used to detect groups of CVs to use in the REVO distance calculation. A method for iteratively improving the accuracy of rate calculations (“Asynchronous weighted ensemble”) is also proposed. Together these developments will constitute a powerful tool for studying long-timescale events in complex biomolecular systems that will be made freely available to other researchers. Through collaborations with experimental partners, this method will be applied to reveal the molecular mechanisms of: i) peptide signaling for a class-B GPCR (Aim 2), and ii) specific recognition of bacterial LPS by a phage tail-spike protein (Aim 3). These mechanisms will inform the design of new molecules with potential therapeutic applications.