Understanding protein folding and function via molecular simulation

该项目在过去一年中涉及以下领域： 1.未折叠蛋白质/隐含溶剂模型。与本·舒勒合作 在ZRICH中，我们开发了一个新的隐式溶剂模型，该模型可以捕获 未折叠蛋白质溶剂化的温度依赖性。这款车 能够半定量地捕捉并解释 观察到随着温度的升高，一组五种蛋白质的崩塌。这 工作在Wuttke等人(5)中进行了描述。预计这一模式将证明 更普遍地用于描述本质上的物理属性 无序的蛋白质。 2.发展了一种研究偶联折叠结合的分子方法 在这些蛋白质能够结合的情况下，天生无序的蛋白质 多个目标。这一方法已被应用于研究分子间的结合 转录因子到共激活子，并在Knott&Best中描述 (3)。 3.蛋白质折叠动力学的一个关键未解决的方面是 链条内的相互作用会减缓折叠速度，这就是所谓的“内耗”。这 已经在最近的几个实验中被检测到，但没有确定的 解释一下。我们已经使用分子模拟来研究这个问题， 并发现所有蛋白质中内耗的一个共同来源是 能源格局中局部扭转障碍的跨越，见 De Sancho等人(6)。我们目前正在扩展这项工作，试图 来解释从蛋白质到蛋白质的内耗变化。 4.与David de Sancho(剑桥)和Jochen Blumberger合作 (伦敦大学学院)我们一直在调查气体的扩散 分子被转移到氢酶的活性部位。我们的方法论 正在开发中的也将普遍适用于研究扩散的任何 酶中的底物分子，并将与一个 结合的化学步骤的描述(参考文献4)获得完整的 结合动力学和机理图。

The project has addressed the following areas in the past year: 1. Unfolded proteins/implicit solvent models. In collaboration with Ben Schuler in Zrich, we have developed a new implicit solvent model which can capture the temperature-dependence of the solvation of unfolded proteins. This model was able to semi-quantitatively capture and provide an explanation for the observed collapse of a set of five proteins as temperature is increased. This work is described in Wuttke et al (5). It is anticipated that this model will prove useful more generally in describing the physical properties of intrinsically disordered proteins. 2. We have developed a molecular method for studying coupled folding-binding of intrinsically disordered proteins in cases where these proteins are able to bind to multiple targets. This approach has been applied to study the binding of transcription factors to co-activators, and is described in Knott & Best (3). 3. A key unresolved aspect of protein folding dynamics is the contribution of interactions within the chain to slowing folding, known as 'internal friction'. This has been detected in several recent experiments, however without a conclusive explanation. We have used molecular simulation to investigate this question, and have found that a common origin for internal friction in all proteins is crossing of local torsional barriers in the energy landscape, described in De Sancho et al (6). We are currently extending this work in an attempt to explain the variation in internal friction from protein to protein. 4. In collaboration with David de Sancho (Cambridge) and Jochen Blumberger (University College London) we have been investigating the diffusion of gas molecules to the active sites of hydrogenase enzymes. The methodology we are developing will also be generally applicable to study diffusion of any substrate molecules within enzymes, and will be combined with a description of the chemical step of binding (Ref. 4) to obtain a complete picture of the binding kinetics and mechanism.