Forrey Christopher, Douglas Jack F, Gilson Michael K
Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20903, USA.
Soft Matter. 2012;8(23):6385-6392. doi: 10.1039/C2SM25160D. Epub 2012 May 14.
Non-covalent molecular association underlies a diverse set of biologically and technologically relevant phenomena, including the action of drugs on their biomolecular targets and self- and supra-molecular assembly processes. Computer models employed to model binding frequently use interaction potentials with atomistic detail while neglecting the thermal molecular motions of the binding species. However, errors introduced by this simplification and, more broadly, the thermodynamic consequences of molecular flexibility on binding, are little understood. Here, we isolate the fundamental relationship of molecular flexibility to binding thermodynamics via simulations of simplified molecules with a wide range of flexibilities but the same interaction potential. Disregarding molecular motion is found to generate large errors in binding entropy, enthalpy and free energy, even for molecules that are nearly rigid. Indeed, small decreases in rigidity markedly reduce affinity for highly rigid molecules. Remarkably, precisely the opposite occurs for more flexible molecules, for which increasing flexibility leads to stronger binding affinity. We also find that differences in flexibility suffice to generate binding specificity: for example, a planar surface selectively binds rigid over flexible molecules. Intriguingly, varying molecular flexibility while keeping interaction potentials constant leads to near-linear enthalpy-entropy compensation over a wide range of flexibilities, with the unexpected twist that increasing flexibility produces opposite changes in entropy and enthalpy for molecules in the flexible versus the rigid regime. Molecular flexibility is thus a crucial determinant of binding affinity and specificity and variations in flexibility can lead to strong yet non-intuitive consequences.
非共价分子缔合是一系列生物学和技术相关现象的基础，包括药物对其生物分子靶点的作用以及自组装和超分子组装过程。用于模拟结合的计算机模型经常使用具有原子细节的相互作用势，而忽略了结合物种的热分子运动。然而，这种简化所引入的误差，以及更广泛地说，分子柔性对结合的热力学后果，人们了解得很少。在这里，我们通过对具有广泛柔性但相互作用势相同的简化分子进行模拟，分离出分子柔性与结合热力学之间的基本关系。发现忽略分子运动在结合熵、焓和自由能方面会产生很大误差，即使对于几乎刚性的分子也是如此。实际上，刚性的小幅降低会显著降低对高度刚性分子的亲和力。值得注意的是，对于更柔性的分子，情况恰恰相反，柔性增加会导致更强的结合亲和力。我们还发现，柔性差异足以产生结合特异性：例如，一个平面表面会选择性地结合刚性分子而非柔性分子。有趣的是，在保持相互作用势不变的情况下改变分子柔性会在很宽的柔性范围内导致近乎线性的焓 - 熵补偿，有一个意想不到的转折是，对于柔性区域和刚性区域的分子，柔性增加会在熵和焓上产生相反的变化。因此，分子柔性是结合亲和力和特异性的关键决定因素，柔性的变化会导致强烈但非直观的后果。
