DSIMB, INSERM, U665, Paris, F-75015, France, DSIMB, INSERM, U665, Faculté des Sciences et Technologies, Université de la Réunion, 15, avenue René Cassin, BP 7151 97715 Saint Denis Messag Cedex 09, La Réunion, France, INTS, Paris, F-75015, France, and Laboratoire de Biochimie et Génétique Moléculaire, Université de la Réunion, 15, avenue René Cassin, BP 7151 97715 Saint Denis Messag Cedex 09, La Réunion, France.
J Chem Theory Comput. 2011 Mar 8;7(3):725-41. doi: 10.1021/ct100394d. Epub 2011 Jan 31.
We characterized a binding intermediate between the protein FKBP12 and one of its high-affinity ligands by means of molecular dynamics simulations. In such an intermediate, which is expected to form at the end-point of the bimolecular diffusional search, short-range interactions between the molecular partners may play a role in the specificity of recognition as well as in the association rate. Langevin dynamics simulations were carried out to generate the intermediate by applying an external biasing force to unbind the ligand from the protein. The intermediate was then refined by seven independent molecular dynamics simulations performed with an explicit solvent model. We found consistent results both for the structure of the protein and for the position of the ligand in the intermediate. The two carbonyl oxygens O2 and O3 of the ligand core region act as two main anchors, making permanent contacts in the intermediate. The transient contacts with the protein are made by the ligand noncore moieties whose structures and mobilities enable many alternative contacts of different types to be formed: π-π molecular overlap and weak hydrogen bonds NH···π, CH···π, and CH···O. Hence, the stability of the ligand at the entrance of the protein binding pocket offers the possibility of fine-tuning a variety of short-range contacts that involve the ligand noncore moieties. Under the hypothesis that the stability of this intermediate is related to the affinity of the ligand, this binding intermediate model comes closest to explaining the role played by the noncore moieties in the affinity of this ligand. Moreover, this model also provides a plausible explanation for how structurally diverse core motifs that all share the carbonyl atoms O2 and O3 bind to FKBP12.
我们通过分子动力学模拟来描述 FKBP12 蛋白与其高亲和力配体之间的一个结合中间态。在这种中间态中，配体可能会在双分子扩散搜索的终点形成，分子伴侣之间的短程相互作用可能在识别特异性以及结合速率方面发挥作用。我们应用外部偏置力将配体从蛋白质上解吸，通过 Langevin 动力学模拟来生成中间态。然后，我们使用显式溶剂模型进行了七次独立的分子动力学模拟来对中间态进行细化。我们得到了一致的结果，包括蛋白质结构和中间态中配体的位置。配体核心区域的两个羰基氧 O2 和 O3 作为两个主要的锚点，在中间态中形成永久性的接触。配体非核心部分与蛋白质的瞬时接触，其结构和迁移率使得可以形成多种不同类型的替代接触：π-π 分子重叠和弱氢键 NH···π、CH···π 和 CH···O。因此，配体在蛋白质结合口袋入口处的稳定性提供了微调涉及配体非核心部分的多种短程接触的可能性。根据这种中间态的稳定性与配体亲和力相关的假设，这种结合中间态模型最接近解释配体中非核心部分在亲和力中所起的作用。此外，该模型还为具有共享羰基原子 O2 和 O3 的不同核心结构基序如何与 FKBP12 结合提供了一个合理的解释。
