Theoretical Physics and Center for Biophysics, Saarland University, Saarbrücken 66123, Germany.
J Chem Inf Model. 2023 Aug 28;63(16):5319-5330. doi: 10.1021/acs.jcim.3c00880. Epub 2023 Aug 10.
The emergence of multidrug-resistant pathogens led to a critical need for new antibiotics. A key property of effective antibiotics against Gram-negative bacteria is their ability to permeate through the bacterial outer membrane via transmembrane porin proteins. Molecular dynamics (MD) simulations are, in principle, capable of modeling antibiotic permeation across outer membrane porins (OMPs). However, owing to sampling problems, it has remained challenging to obtain converged potentials of mean force (PMFs) for antibiotic permeation across OMPs. Here, we investigated the convergence of PMFs along a single collective variable aimed at quantifying the permeation of the antibiotic fosmidomycin across the OprO porin. We compared standard umbrella sampling (US) with three advanced flavors of the US technique: (i) Hamiltonian replica exchange with solute tempering in combination with US, (ii) simulated tempering-enhanced US, and (iii) replica-exchange US. To quantify the PMF convergence and to reveal hysteresis problems, we computed several independent sets of US simulations starting from pulling simulations in the outward and inward permeation directions. We find that replica-exchange US in combination with well-chosen restraints is highly successful for obtaining converged PMFs of fosmidomycin permeation through OprO, reaching PMFs converged to subkilocalorie per mole accuracy.
多药耐药病原体的出现导致了对新型抗生素的迫切需求。针对革兰氏阴性菌的有效抗生素的一个关键特性是它们能够通过跨膜孔蛋白穿透细菌外膜。原则上，分子动力学（MD）模拟能够模拟抗生素通过外膜孔蛋白（OMP）的渗透。然而，由于采样问题，获得抗生素通过 OMP 渗透的收敛平均力势（PMF）仍然具有挑战性。在这里，我们研究了沿单个集体变量的 PMF 收敛性，旨在量化抗生素福提霉素通过 OprO 孔蛋白的渗透。我们将标准伞状采样（US）与三种先进的 US 技术进行了比较：（i）结合溶质调温和 US 的哈密顿复制交换，（ii）模拟调温增强的 US，以及（iii）复制交换 US。为了量化 PMF 收敛性并揭示滞后问题，我们从向外和向内渗透方向的拉动模拟开始，计算了几组长独立的 US 模拟。我们发现，结合了精心选择的约束条件的复制交换 US 非常成功地获得了福替霉素通过 OprO 渗透的收敛 PMF，达到了收敛到亚千卡每摩尔精度的 PMF。
