Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada.
School of Biological and Chemical Sciences, Queen Mary University of London, London, E1 4NS, UK.
Phys Chem Chem Phys. 2013 Dec 21;15(47):20447-20455. doi: 10.1039/c3cp50868d. Epub 2013 Jun 12.
Penicillin, travels through bodily fluids, targeting and acylatively inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria. Somehow, it avoids metabolic degradation remaining inactive en route. To resolve this ability to switch from a non-active, to a highly reactive form, we investigated the dynamic structure-activity relationship of penicillin by inelastic neutron spectroscopy, reaction kinetics, NMR and multi-scale theoretical modelling (QM/MM and post-HF ab initio). Results show that by a self-activating physiological pH-dependent two-step proton-mediated process, penicillin changes geometry to activate its irreversibly reactive acylation, facilitated by systemic intramolecular energy management and cooperative vibrations. This dynamic mechanism is confirmed by the first ever reported characterisation of an antibiotic by neutrons, achieved on the TOSCA instrument (ISIS facility, RAL, UK).
青霉素可穿透体液，靶向并酰化失活革兰氏阳性菌细胞壁合成所需的酶。不知何故，它在体内运输过程中避免了代谢降解，保持着非活性状态。为了研究青霉素从非活性到高反应性形式的这种转换能力，我们通过非弹性中子散射、反应动力学、NMR 和多尺度理论建模（QM/MM 和后 HF 从头计算）研究了青霉素的动态结构-活性关系。结果表明，通过自身激活的生理 pH 依赖的两步质子介导过程，青霉素通过系统的分子内能量管理和协同振动改变几何形状，从而激活不可逆反应性酰化。这一动态机制通过在 TOSCA 仪器（ISIS 设施，RAL，英国）上首次对抗生素进行的中子散射实验得到证实。
