CAREER: An Integrated Multiscale Platform for Fundamental Studies of Peptide Self-Assembly

“这项奖励是根据2009年美国复苏和再投资法案（公法111-5）资助的。”多肽是一种非常通用的可调节分子自组装的平台，在温度、pH、盐、溶剂和化学添加剂的影响下形成令人印象深刻的各种纳米级形态。此外，它们高度的生物相容性、构象特异性和分子识别使这些系统成为材料、纳米技术、医学和生物技术领域自下而上设计的理想候选者。然而，尽管实验肽工程取得了成功，但缺乏可用于合理设计肽自组装材料的预测性理论理解。具体来说，目前还没有通用的定量方法来理解单个残基突变对组装热力学和动力学的影响，或者预测不同肽可能采用的丰富多样的相形态。智力优势：CAREER项目涉及开发新的多尺度模拟方法，以克服多肽建模的现有障碍，并利用这些方法对多肽自组装的热力学产生新的见解。这项工作发展了一种新的，一般的多尺度方法，严格推导粗粒度肽模型从仔细执行的全原子模拟。该方法的核心是相对熵，这是一种在不同尺度上连接模型的定量度量：优化序列特定的粗粒度模型将通过最小化粗粒度和参考全原子肽二聚体模拟之间的相对熵来开发。开发的简化模型将使大型低聚物组装的长时间尺度研究成为可能，这将为肽自组装热力学提供新的基本分子视角。具体来说，这项工作将研究构象转换肽，这是一类对环境线索敏感的工程肽，可以在不同的自组装纳米结构之间转换。这些多肽的多样性可以描述多肽自组装的基本和序列特定方面，并提供预测模拟的敏感测试。利用所提出的多肽开关的多尺度方法，这项工作将检查序列对相行为和形态的影响，并阐明驱动其自组装的基本物理相互作用。更广泛的影响：这项工作将为多尺度模拟开发一种基础的、严格的新方法，这将不仅对多肽有用，而且对多尺度物理中的许多问题有用，为自组装纳米尺度技术的自底向上合理设计提供重要工具。特别是对于多肽，这项工作将首次将精确的，收敛的所有原子模拟与多尺度粗粒度模拟结合起来，并将为单肽结构和自组装驱动力的复杂平衡提供新的视角。仅从序列预测肽组装将使材料和生物学中的合理肽设计工作成为可能。这个项目的工作将与几项教育倡议并行。PI将开发新的研究生分子模拟选修课和分子热力学在线文本，强调多尺度物理，并利用肽作为自组装，溶液热力学，聚合物物理，纳米材料，生物物理学和物理化学的广泛例子。PI将继续利用UCSB成功的研究项目，如研究生研究实习项目，将本科生（迄今为止有4名，其中包括一名女性）和少数族裔学生（迄今为止有一名暑期硕士学生）纳入他的研究。与佛罗里达农工大学小组的个人合作将进一步从该机构招募代表性不足的少数民族参加PI小组的夏季研究。PI还将继续参与UCSB的夏季本科生研究研讨会和K-12外展项目。最后，PI将发起年度部门研究生研讨会，以扩大博士候选人的研究范围。

0845074Shell"This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)."An Integrated Multiscale Platform for Fundamental Studies of Peptide Self Assembly Peptides are exceptionally versatile platforms for tunable molecular self assembly, forming an impressive variety of nanoscale morphologies in response to cues spanning temperature, pH, salt, solvent, and chemical additives. Moreover, their high degrees of biocompatibility, conformational specificity, and molecular recognition have made these systems ideal candidates for bottom up design in materials, nanotechnology, medicine, and biotechnology. Yet despite successes in experimental peptide engineering, a predictive theoretical understanding that could be used to rationally design peptide self assembled materials is lacking. Specifically, there are no general, quantitative methods for understanding the impact of single residue mutations on assembly thermodynamics and kinetics, or for predicting the rich, diverse phase morphologies that different peptides can adopt.Intellectual Merit:The CAREER project involves the development of new multiscale simulation methods to overcome existing barriers to multipeptide modeling, and the use of these to generate new insights into the thermodynamics of peptide self assembly. This work develops a novel, general multiscale methodology that rigorously derives coarse grained peptide models from carefully performed all-atom simulations. At the heart of this approach is the relative entropy, a quantitative metric for linking models at different scales: optimized sequence specific coarse grained models will be developed by minimizing the relative entropy between coarse grained and reference all atom peptide dimer simulations. The reduced models developed will enable long time scale studies of large oligomeric assemblies that will provide new fundamental molecular perspectives on peptide self-assembly thermodynamics. Specifically, this work will study conformational switching peptides, a class of engineered peptides that react sensitively to environmental cues to transform among different self assembled nanostructures. The diversity of these peptides stands to delineate fundamental and sequence specific aspects of peptide self assembly, and provides a sensitive test of predictive simulations. Using the proposed multiscale methodology for switching peptides, this work will examine sequence effects on phase behavior and morphologies, and elucidate the basic physical interactions that drive their self-assembly.Broader Impacts:This work will develop a fundamental, rigorous new approach to multiscale simulation that will be useful not only for peptides, but for many problems in multiscale physics, offering an important tool for bottom up rational design of nanoscale technologies built on self assembly. For peptides specifically, this work will be the first to couple accurate, converged all atom simulations with multiscale coarse grained ones, and will generate new perspectives on the complex balance of single peptide structure and self assembly driving forces. The prediction of peptide assembly from sequence alone will enable rational peptide design efforts in materials and biology. Work on this project will parallel several educational initiatives. The PI will develop a new graduate molecular simulation elective and online text on molecular thermodynamics that emphasize multiscale physics and leverage peptides as broad examples of self-assembly, solution thermodynamics, polymer physics, nanomaterials, biophysics, and physical chemistry. The PI will continue to use successful research programs at UCSB, such as the Graduate Research Internship Program, to incorporate undergraduates (four so far, including one female)and underrepresented minority students (one summer masters student thus far) in his research. An individual collaboration with a Florida A&M University group will further recruit underrepresented minorities from that institution for summer research in the PI's group. The PI will also continue participation in UCSB's summer undergraduate research seminars and K-12 outreach programs. Finally, the PI will initiate an annual departmental graduate symposium to broaden the reach of research by Ph.D. candidates.