Dipartimento di Fisica, Università degli Studi di Cagliari, Campus Monserrato, I-09042 Monserrato, Italy.
J Phys Condens Matter. 2012 Mar 14;24(10):104012. doi: 10.1088/0953-8984/24/10/104012. Epub 2012 Feb 21.
Many relevant biological processes take place on time scales not reachable by standard all-atom computer simulations. The translocation of antibiotics through non-specific bacterial porins is an example. Microscopic effects compete to determine penetration routes and, consequently, free energy barriers to be overcome. Since bacteria can develop resistance to treatment also by reducing their antibiotic permeability, to understand the microscopic aspects of antibiotic translocation is an important step to rationalize drug design. Here, to investigate the translocation we propose a complete numerical model that combines the diffusion-controlled rate theory and a kinetic Monte Carlo scheme based on both experimental data and microscopically well-founded all-atom simulations. Within our model, an antibiotic translocating through an hour-glass-shaped channel can be described as a molecule moving on a potential of mean force featuring several affinity sites and a high central barrier. The implications of our results for the characterization of antibiotic translocation at in vivo concentrations are discussed. The presence of an affinity site close to the mouth of the channel seems to favor the translocation of antibiotics, the affinity site acting as a particle reservoir. Possible connections between results and the appearance of mutations in clinical strains are also outlined.
许多相关的生物过程发生在标准全原子计算机模拟无法达到的时间尺度上。抗生素通过非特异性细菌孔蛋白的转运就是一个例子。微观效应相互竞争，以确定穿透途径，从而确定需要克服的自由能势垒。由于细菌也可以通过降低抗生素通透性来产生耐药性，因此了解抗生素转运的微观方面是合理化药物设计的重要步骤。在这里，为了研究转运，我们提出了一个完整的数值模型，该模型结合了扩散控制速率理论和基于实验数据和微观合理的全原子模拟的动力学蒙特卡罗方案。在我们的模型中，一种通过沙漏形通道转运的抗生素可以被描述为一种在具有多个亲和位点和高中心势垒的平均力势上移动的分子。我们的结果对于在体内浓度下描述抗生素转运的特征的影响进行了讨论。通道口附近存在亲和位点似乎有利于抗生素的转运，亲和位点充当粒子储库。还概述了结果与临床菌株出现突变之间的可能联系。
