Atomistic structures and dynamics of biomolecules from low-resolution scattering data

来自低分辨率散射数据的生物分子的原子结构和动力学

• 批准号: 207700222
• 负责人: Professor Dr. Jochen Hub
• 金额: --
• 依托单位: Institut für Biophysik
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/207700222?language=en
• 关键词: Atomistic; structures; dynamics; biomolecules; low

The interplay between experiment and simulation has developed to an important driving force for biomolecular research, yet with recent developments new challenges arise. For instance, the interest in structures of large biomolecular assemblies or membrane proteins has augmented the requirement to interpret low-resolution scattering data, because crystals of such structures frequently diffract poorly. Likewise, the emerging technique of time-resolved wide-angle X-ray scattering (TR-WAXS) can in principle measure conformational transitions of proteins in solution at near-atomic resolution, yet the reduced TR-WAXS spectra are difficult to interpret at a molecular level. Within the Emmy-Noether group, we will apply molecular dynamics (MD) simulations and related computational methods to interpret such X-ray scattering data that alone provide only reduced information. In particular, we will develop new refinement algorithms, that aim to overcome the limitations of current refinement protocols at low resolution. The key essence of these algorithms will be to reduce the dimensionality of the search space using a correlation analysis, in order to concentrate the sampling within a low-dimensional configurational space, where a successful refinement is more promising. Complementary to these efforts to refine static structures, we will apply measured TR-WAXS spectra as additional driving forces into MD simulations, to yield an unbiased interpretation of the WAXS data at atomic detail. We will focus that analysis on proton pumps such as rhodopsin, and we thus aim to derive the structural cycle of these important membrane proteins based on only a single experiment. Apart from the focus on the interpretation of X-ray data, I aim to build upon my previous studies on the selectivity of membrane channels within this Emmy-Noether grant. Using extensive MD simulations, we first aim to identify the selectivity filters and mechanisms of a set of membrane channels, including a urea transporter, the formate channel FocA, and a beta-barrel pore. In a second step we will use the understanding of molecular filters, in order to rationally design a molecular filter from scratch with preselected selectivity characteristics.

实验与模拟之间的相互作用已发展成为生物分子研究的重要驱动力，但随着最近的发展，新的挑战也随之出现。例如，对大型生物分子组装体或膜蛋白结构的兴趣增加了解释低分辨率散射数据的要求，因为此类结构的晶体通常衍射性能很差。同样，新兴的时间分辨广角 X 射线散射 (TR-WAXS) 技术原则上可以以近原子分辨率测量溶液中蛋白质的构象转变，但简化的 TR-WAXS 光谱很难在分子水平上解释。在 Emmy-Noether 小组内，我们将应用分子动力学 (MD) 模拟和相关计算方法来解释此类仅提供有限信息的 X 射线散射数据。特别是，我们将开发新的细化算法，旨在克服当前细化协议在低分辨率下的局限性。这些算法的关键本质是使用相关分析来降低搜索空间的维数，以便将采样集中在低维配置空间内，在低维配置空间中成功的细化更有希望。作为对这些细化静态结构的努力的补充，我们将应用测量的 TR-WAXS 光谱作为 MD 模拟的额外驱动力，以在原子细节上对 WAXS 数据进行公正的解释。我们将重点分析视紫红质等质子泵，因此我们的目标是仅基于一次实验就推导出这些重要膜蛋白的结构循环。除了重点关注 X 射线数据的解释之外，我的目标是在艾美-诺特奖的资助下，以我之前关于膜通道选择性的研究为基础。通过广泛的 MD 模拟，我们首先旨在确定一组膜通道的选择性过滤器和机制，包括尿素转运蛋白、甲酸盐通道 FocA 和 β 桶孔。在第二步中，我们将利用对分子过滤器的理解，以便从头开始合理地设计具有预选选择性特性的分子过滤器。

项目成果

A glycerophospholipid-specific pocket in the RVFV class II fusion protein drives target membrane insertion

• DOI: 10.1126/science.aal2712
• 发表时间: 2017-11-03
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Guardado-Calvo, P.;Atkovska, K.;Rey, F. A.
• 通讯作者: Rey, F. A.

Ultrafast anisotropic protein quake propagation after CO photodissociation in myoglobin

• DOI: 10.1073/pnas.1603539113
• 发表时间: 2016-09-20
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Brinkmann, Levin U. L.;Hub, Jochen S.
• 通讯作者: Hub, Jochen S.