Using NMR-derived restraints in combination with molecular dynamics simulations to derive thermodynamic parameters for biomolecular interactions.

复杂的生物过程涉及一个分子与另一个分子的结合。结合过程可以被认为是一个“形状”问题，因此结合的强度关键取决于配体和蛋白质上的结合口袋之间的形状互补。然而，结合过程要比这复杂得多，因为它还取决于相互作用伙伴的动态程度(软性)。测量蛋白质动力学对结合的贡献的一项有价值的技术涉及高分辨率核磁共振(核磁共振)弛豫时间测量。然而，这种测量的解释需要对分子运动的性质有一些了解，而且在过去，为这些运动假定一个简化的模型是常见的做法。在这里，我们建议使用受实验核磁共振数据约束的理论分子动力学模拟。这样的模拟将提供更真实的图像，在蛋白质的配基结合之前和之后发生的运动过程，并将允许更准确的量化影响结合过程的动态因素。这些信息在基于结构的新药先导化合物发现的背景下具有重要意义。

Complex biological processes involve the binding of one molecule by another. The binding process can be thought of as a 'shape' problem, whereby the strength of binding depends critically on shape complementarity between the ligand and the binding pocket on the protein. However, the binding process is more complicated than this, since it is also determined by the extent of dynamics ('floppiness') of the interacting partners. A valuable technique to measure the contribution of protein dynamics to binding concerns high-resolution nuclear magnetic resonance (NMR) relaxation-time measurements. However, the intepretation of such measurements requires some knowledge of the nature of the molecular motions, and in the past it has been common practice to assume a simplified model for these motions. Here, we propose to make use of theoretical molecular dynamics simulations which are restrained by the experimental NMR data. Such simulations will offer a much more realistic picture of the motional processes that take place in the protein before and after ligand binding, and will permit a more accurate quantitation of the dynamic factors that influence the binding process. Such information is of significant importance in the context of structure-based discovery of lead compounds for novel drugs.