Temperature Accelerated Sliced Sampling to Probe Ligand Dissociation from Protein

被引：2

作者：

Tripathi, Shubhandra ^{[1
]}

Nair, Nisanth N. ^{[1
]}

机构：

[1] Indian Inst Technol Kanpur, Dept Chem, Kanpur 208016, India

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2023年 / 63卷 / 16期

关键词：

FREE-ENERGY CALCULATIONS; C BETA-LACTAMASES; MOLECULAR-DYNAMICS; BINDING PROCESS; ACTIVE-SITE; RARE EVENTS; MECHANISM; METADYNAMICS; KINETICS; EFFICIENT;

D O I：

10.1021/acs.jcim.3c00376

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Modelingligand unbinding in proteins to estimate the free energyof binding and probing the mechanism presents several challenges.They primarily pertain to the entropic bottlenecks resulting fromprotein and solvent conformations. While exploring the unbinding processesusing enhanced sampling techniques, very long simulations are requiredto sample all of the conformational states as the system gets trappedin local free energy minima along transverse coordinates. Here, wedemonstrate that temperature accelerated sliced sampling (TASS) isan ideal approach to overcome some of the difficulties faced by conventionalsampling methods in studying ligand unbinding. Using TASS, we studythe unbinding of avibactam inhibitor molecules from the Class C & beta;-lactamase(CBL) active site. Extracting CBL-avibactam unbinding free energetics,unbinding pathways, and identifying critical interactions from theTASS simulations are demonstrated.

引用

页码：5182 / 5191

页数：10

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