Solvation modeling for next-gen biomolecule simulations

项目总结/摘要 计算生物物理学和药物发现需要更快，更好，在某些情况下， 蛋白质溶剂化和蛋白质-蛋白质相互作用的完全重新制定的物理建模： 用于设计大环化合物，可以夹在大的蛋白质-蛋白质界面中; 模拟生物化学途径;用于计算多抗体运动、结合和识别; 用于配制针对折叠和聚集不稳定性的治疗性蛋白质溶液;以及 减轻蛋白质聚集的疾病。 快速、准确和可扩展地建模大型或复杂的蛋白质， 骨料，并在水中，需要一个团队，可以从四个主要是非创新， 重叠的研究领域：原子蛋白质MD，蛋白质-蛋白质对接，蛋白质-胶体 液态理论和水统计力学。将这些方法结合起来， 在生物相关的时间和空间上快速准确的计算机建模的进展 尺度，具有适当的统计力学。在这里，我们的团队是6个PI， 高度合作（42份联合论文），每一份都带来了最前沿的能力（Simmerling，一个关键的 开发人员或AMBER和GBNECK; Kozakov，CLUSPRO开发人员，顶级蛋白质-蛋白质相互作用 卡普里中的网络服务器; Crachas，数学几何学家，其BRIKARD提供了证明的加速， Hribar-Lee的Wertheim理论成功地预测了简单的 蛋白质聚集; Fennell，SEA的开发者，一个快速准确的水模型; Dill， 水和MELD（一种已被证明成功的MD加速器）的统计力学模型 在CASP中）。 我们的5年目标包括：（A）超越刚性蛋白质-蛋白质对接，包括 构象灵活性、原子细节、大系统的可扩展性和亲和力。(B)预测 蛋白质和抗体聚集热点以及对盐和赋形剂的依赖性。（丙） 使用下一代隐式溶剂开发AmberSB力场，更快，更准确 表面积计算，在CASP，SAMPL和卡普里事件中进行盲测。(D)发展中 用于溶液平衡和水动力学的“超快速”分析水模型，例如 扩散、粘度和在表面和通过孔隙的运输。团队管理计划是 建议通过协调一致的领导来优化合作研究，并提供持续的 沟通、参与和集体智慧的发展。

Project Summary / Abstract Computational biophysics and drug discovery need much faster, better, and in some cases completely reformulated physical modeling of protein solvation and of protein-protein interactions: for designing macrocyclic compounds that can sandwich into large protein-protein interfaces; for modeling biochemical pathways; for computing multi-antibody motions, binding and recognition; for formulating therapeutic protein solutions against folding and aggregation instabilities; and to mitigate against diseases of protein aggregation. Achieving fast, accurate and scalable modeling of proteins that are large or in complexes or aggregates, and that are in water, requires a team that can innovate from four largely non- overlapping research communities: atomistic protein MD, protein-protein docking, protein-colloid liquid-state theory, and water statistical mechanics. Combining these approaches is needed for big advances toward fast and accurate computer modeling on biologically relevant time and space scales, with proper statistical mechanics. Here, our team is 6 PIs that have already been pairwise highly collaborative (42 joint papers), and that each bring forefront capabilities (Simmerling, a key developer or AMBER and GBNECK; Kozakov, developer of CLUSPRO, top protein-protein interaction webserver in CAPRI; Coutsias, mathematical geometer whose BRIKARD gives proven acceleration of constrained search by 100x; Hribar-Lee, whose Wertheim Theory successfully predicts simple protein aggregation; Fennell, developer of SEA, a fast accurate water model; and Dill, developer of statistical mechanical models of water and of MELD, an MD accelerator that has proven successful in CASP). Our 5-year Aims include: (A) Going beyond rigid protein-protein docking, to include conformational flexibility, atomic detail, scalability to large systems, and affinities. (B) Predicting protein and antibody aggregation hot-spots and dependencies on salts and excipients. (C) Developing AmberSB force fields with next generation implicit solvent, and faster, more accurate surface-area calculations, with blind testing in CASP, SAMPL and CAPRI events. (D) Developing ‘super-fast’ analytical water models for solution equilibria, and for water dynamics, such as diffusion, viscosities and transport at surfaces and through pores. A Team Management Plan is proposed to optimize collaborative research with concerted leadership, and to provide for ongoing communication, engagement and the development of collective intelligence.