CAREER - New Methods for Simulating Biomolecules of Several Microns in Length

分子功能的相当大一部分涉及在宽范围的长度尺度上的运动，例如，从化学键的振动到超分子复合物的整体构象变化，再到宏观的肌肉收缩。这项研究的目标是引入几种新的计算方法，用于描述任何期望长度尺度的运动，而不会丢失原子计算的细节，这是前所未有的模拟能力。该方法的核心是子结构综合法，它把给定的结构看作是以某种方式共同作用的子结构的集合。亚结构的选择是任意的，有时是很自然的，例如超分子复合物中的结构域或亚基。首先，每个子结构的振动模式是通过求解本征值问题来确定的。接下来，通过一组约束将各种子结构连接在一起，以在子结构间接口处强制几何兼容性。组装结构的模式，然后可以使用一组低频子结构模式的瑞利-里兹原理计算。在计算上，这代表了一个更可取的问题比解决组装结构的完整的特征值问题。这种新的方法将被应用到F-肌动蛋白，一个典型的几微米的丝状系统，研究其在任何长度的机械和动力学特性。这也将有助于解释测量分子弹性性质的实验。模拟大尺度运动的新方法不仅对分子动力学的研究产生影响，而且将对生物工程和化学领域做出重大贡献。此外，由于所提出的方法中的一些概念与机械工程领域中的概念相关，因此将其实现为用于描述复杂分子的运动的方法需要包括生物学、物理学和工程学在内的多个学科的知识。因此，该项目的成功将是创造性思维和解决问题的一个很好的例子，得益于跨学科的沟通。受益者将不仅是直接参与项目的受训人员，而且是具有不同背景的更多受众，他们对生命科学和工程问题普遍感兴趣，但从非常不同的角度。特别是，它将使本科生接触到跨学科研究的概念。最后，一个更广泛的社区将达到通过公开发行的计算机软件开发的这项工作。

A substantial part of molecular functions involves motions in a wide range of length scales, e.g., from the vibrations of chemical bonds to global conformational changes of supermolecular complexes to macroscopic muscle contractions. The goal of this research is to introduce several new computational methods for describing the motions at any desired length scale without losing the details of atomic calculations, which is an unprecedented simulation capacity. The central method is substructure synthesis method that regards a given structure as an assemblage of substructures acting together in some ways. The choice of substructures is arbitrary, and sometimes quite natural, such as domains or subunits in supermolecular complexes. First, the vibrational modes for each substructure are determined by solving an eigenvalue problem. Next, various substructures are joined together by a set of constraints to enforce geometric compatibility at the inter-substructure interfaces. The modes for the assembled structure can then be computed by the Rayleigh-Ritz principle using a set of low-frequency substructure modes. Computationally, this represents a much more desirable problem than solving the full eigenvalue problem for the assembled structure. This new methods will be applied to F-actin, a typical filamentous system of several microns, to study its mechanical and dynamic properties at any length. This will also help interpret the experiments that measure molecular elastic properties. The new methods for simulating motions in a wide range of length scales will not only have an impact on the study of molecular dynamics, but also will significantly contribute to the fields of bioengineering and chemistry. Moreover, since some concepts in the proposed methods are related to those in the mechanical engineering field, their implementation as methods for describing motions of complex molecules requires knowledge of multiple disciplines including biology, physics, and engineering. The success of this project will therefore be an excellent example of creative thinking and problem solving benefited from interdisciplinary communication. The beneficiaries will not only be the trainees who are directly involved in the project, but also a larger audience with diverse background who are commonly interested in problems in life sciences and engineering, but from very different perspectives. Particularly, it will expose undergraduate students to concepts of interdisciplinary research. Finally, a broader community will be reached via public distribution of the computer software developed in this work.