Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India.
J Chem Inf Model. 2023 Aug 28;63(16):5182-5191. doi: 10.1021/acs.jcim.3c00376. Epub 2023 Aug 4.
Modeling ligand unbinding in proteins to estimate the free energy of binding and probing the mechanism presents several challenges. They primarily pertain to the entropic bottlenecks resulting from protein and solvent conformations. While exploring the unbinding processes using enhanced sampling techniques, very long simulations are required to sample all of the conformational states as the system gets trapped in local free energy minima along transverse coordinates. Here, we demonstrate that temperature accelerated sliced sampling (TASS) is an ideal approach to overcome some of the difficulties faced by conventional sampling methods in studying ligand unbinding. Using TASS, we study the unbinding of avibactam inhibitor molecules from the Class C β-lactamase (CBL) active site. Extracting CBL-avibactam unbinding free energetics, unbinding pathways, and identifying critical interactions from the TASS simulations are demonstrated.
在蛋白质中模拟配体的解吸以估计结合自由能并研究机制存在一些挑战。它们主要涉及由于蛋白质和溶剂构象而产生的熵瓶颈。在使用增强采样技术探索解吸过程时，由于系统在横向坐标上的局部自由能最小值中被捕获，因此需要进行非常长的模拟才能采样所有构象状态。在这里，我们证明温度加速切片采样（TASS）是克服传统采样方法在研究配体解吸时面临的一些困难的理想方法。使用 TASS，我们研究了阿维巴坦抑制剂分子从 C 类β-内酰胺酶（CBL）活性位点的解吸。从 TASS 模拟中提取 CBL-阿维巴坦解吸自由能、解吸途径，并确定关键相互作用。
