Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Am Chem Soc. 2013 Apr 24;135(16):6084-91. doi: 10.1021/ja311327v. Epub 2013 Apr 10.
Methonium (N(+)Me3) is an organic cation widely distributed in biological systems. As an organic cation, the binding of methonium to protein receptors requires the removal of a positive charge from water. The appearance of methonium in biological transmitters and receptors seems at odds with the large unfavorable desolvation free energy reported for tetramethylammonium (TMA(+)), a frequently utilized surrogate of methonium. Here, we report an experimental system that facilitates incremental internalization of methonium within the molecular cavity of cucurbit[7]uril (CB[7]). Using a combination of experimental and computational studies, we show that the transfer of methonium from bulk water (partially solvated methonium state) to the CB[7] cavity (mostly desolvated methonium state) is accompanied by a remarkably small desolvation enthalpy of just 0.5 ± 0.3 kcal·mol(-1), a value significantly less endothermic than those values suggested from gas-phase model studies. Our results are in accord with neutron scattering measurements that suggest methonium produces only a minimal perturbation in the bulk water structure, which highlights the limitations of gas-phase models. More surprisingly, the incremental withdrawal of the methonium surface from water produces a nonmonotonic response in desolvation enthalpy. A partially desolvated state exists, in which a portion of the methonium group remains exposed to solvent. This structure incurs an increased enthalpic penalty of ~3 kcal·mol(-1) compared to other solvation states. We attribute this observation to the pre-encapsulation dewetting of the methonium surface. Together, our results offer a rationale for the wide distribution of methonium in a biological context and suggest limitations to computational estimates of binding affinities based on simple parametrization of solvent-accessible surface area.
甲铵（N(+)Me3）是一种广泛存在于生物系统中的有机阳离子。作为一种有机阳离子，甲铵与蛋白受体的结合需要从水中去除正电荷。甲铵在生物递质和受体中的出现似乎与四甲基铵（TMA(+)）报道的大不利去溶剂自由能不一致，TMA(+) 是甲铵的常用替代品。在这里，我们报告了一个实验系统，该系统有助于甲铵在葫芦[7]脲（CB[7]）的分子腔内逐渐内化。通过实验和计算研究的结合，我们表明甲铵从本体水（部分溶剂化甲铵状态）转移到 CB[7]腔（主要去溶剂化甲铵状态）伴随着非常小的去溶剂化焓，仅为 0.5±0.3 kcal·mol(-1)，这比气相模型研究提出的值明显更吸热。我们的结果与中子散射测量结果一致，表明甲铵仅对本体水结构产生最小的干扰，这突出了气相模型的局限性。更令人惊讶的是，甲铵表面从水中逐渐撤出会导致去溶剂化焓呈非单调响应。存在部分去溶剂化状态，其中一部分甲铵基团仍暴露于溶剂中。与其他溶剂化状态相比，这种结构会产生约 3 kcal·mol(-1)的额外焓罚。我们将这一观察归因于甲铵表面的预包封去湿。总之，我们的结果为甲铵在生物学背景下的广泛分布提供了一个理由，并表明基于简单参数化溶剂可及表面积的结合亲和力计算估计存在局限性。
