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

0845074壳牌“该奖项是根据2009年美国复苏和再投资法案(公共法律111-5)资助的。”多肽自组装肽的综合多尺度基础研究平台是非常通用的可调分子自组装平台，可根据温度、pH、盐、溶剂和化学添加剂的提示形成令人印象深刻的各种纳米级形貌。此外，它们高度的生物兼容性、构象特异性和分子识别能力使这些系统成为材料、纳米技术、医学和生物技术中自下而上设计的理想候选者。然而，尽管在试验性多肽工程方面取得了成功，但可用于合理设计多肽自组装材料的预测性理论理解仍然缺乏。具体地说，目前还没有通用的定量方法来了解单个残基突变对组装热力学和动力学的影响，也没有通用的定量方法来预测不同多肽可以采用的丰富、多样化的相形态。智力优势：该职业项目涉及开发新的多尺度模拟方法来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。这项工作开发了一种新颖的、通用的多尺度方法，从仔细执行的全原子模拟中严格推导出粗粒多肽模型。这种方法的核心是相对熵，这是一种用于连接不同尺度模型的定量度量：通过最小化粗粒度和参考所有原子多肽二聚体模拟之间的相对熵，将开发出优化的特定于序列的粗粒度模型。开发的简化模型将使大规模低聚物组装的长时间研究成为可能，这将为肽自组装热力学提供新的基本分子观点。具体地说，这项工作将研究构象转换肽，这是一类对环境线索反应敏感的工程化多肽，可以在不同的自组装纳米结构之间进行转换。这些多肽的多样性将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。使用所提出的多尺度切换多肽方法，这项工作将检验序列对相行为和形态的影响，并阐明驱动它们自组装的基本物理相互作用。广泛影响：这项工作将开发一种基本的、严格的多尺度模拟新方法，不仅对多肽有用，而且对多尺度物理中的许多问题都有用，为基于自组装的纳米级技术的自下而上的合理设计提供了重要的工具。具体地说，这项工作将首次将准确、收敛的所有原子模拟与多尺度粗颗粒模拟相结合，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。仅从序列预测多肽组装就可以在材料和生物学上进行合理的多肽设计。该项目的工作将与几项教育倡议并行。PI将开发一门关于分子热力学的新的研究生分子模拟选修课和在线文本，强调多尺度物理，并利用多肽作为自组装、溶液热力学、聚合物物理、纳米材料、生物物理和物理化学的广泛例子。PI将继续使用UCSB成功的研究项目，如研究生研究实习计划，将本科生(到目前为止有四名，包括一名女性)和代表不足的少数族裔学生(到目前为止有一名夏季硕士学生)纳入他的研究。与佛罗里达农工大学一个团体的个人合作，将进一步从该机构招募代表人数较少的少数族裔，在该团体的夏季研究中使用。PI还将继续参加UCSB的暑期本科生研究研讨会和K-12外展计划。最后，PI将发起一年一度的系毕业生研讨会，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.