QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations.
QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations.
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DOI：
10.1039/d3sc04195f
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发表时间：
2023-11-22
期刊：
影响因子：
8.4
通讯作者：
Amaro RE
中科院分区：
文献类型：
--
作者：
Ojha AA;Votapka LW;Amaro RE
了解配体与生物分子的相互作用是药物发现和开发的一个组成部分。计算与药物相关的受体-配体复合物的热力学和动力学量的挑战包括配体的大小和灵活性、受体的大规模构象重排、准确的力场参数、模拟效率以及与罕见事件相关的足够的采样。我们最近开发的多尺度里程碑模拟方法SEEKR2 （simulation Enabled Estimation of Kinetic Rates v.2）已经证明，通过在靠近结合位点的区域采用分子动力学（MD）模拟，可以成功预测解结合（koff）动力学。MD区域进一步细分为更小的Voronoi镶嵌，以提高模拟效率和并行化。迄今为止，所有的分子力学模拟都是使用一般分子力学力场来运行的。结合量子力学方法，通过重新参数化结合态的配体部分电荷来产生系统特有的力场，可以进一步提高计算的准确性。力场重参数化过程改变了双分子复合物的势能格局，使分子间相互作用和束缚态的极化效应能够更准确地表征。我们提出了QMrebind （Quantum Mechanical force field reparameterization at receptor -配体结合位点），这是一个基于orca的软件，它有助于在代表受体-配体复合物结合状态的相空间内重新参数化势能函数。利用SEEKR2 koff估计和实验确定的动力学速率，我们比较和解释了利用新重新参数化的力场获得的模型宿主-客体系统和hsp90抑制剂复合物的受体-配体解结合动力学。该方法为预测受体-配体的科夫速率常数提供了更高的精度。受体（灰色）-配体（黄色）复合物相空间划分为MD区（进一步划分为Voronoi细胞）和BD区的图形表示。
Understanding the interaction of ligands with biomolecules is an integral component of drug discovery and development. Challenges for computing thermodynamic and kinetic quantities for pharmaceutically relevant receptor–ligand complexes include the size and flexibility of the ligands, large-scale conformational rearrangements of the receptor, accurate force field parameters, simulation efficiency, and sufficient sampling associated with rare events. Our recently developed multiscale milestoning simulation approach, SEEKR2 (Simulation Enabled Estimation of Kinetic Rates v.2), has demonstrated success in predicting unbinding (koff) kinetics by employing molecular dynamics (MD) simulations in regions closer to the binding site. The MD region is further subdivided into smaller Voronoi tessellations to improve the simulation efficiency and parallelization. To date, all MD simulations are run using general molecular mechanics (MM) force fields. The accuracy of calculations can be further improved by incorporating quantum mechanical (QM) methods into generating system-specific force fields through reparameterizing ligand partial charges in the bound state. The force field reparameterization process modifies the potential energy landscape of the bimolecular complex, enabling a more accurate representation of the intermolecular interactions and polarization effects at the bound state. We present QMrebind (Quantum Mechanical force field reparameterization at the receptor–ligand binding site), an ORCA-based software that facilitates reparameterizing the potential energy function within the phase space representing the bound state in a receptor–ligand complex. With SEEKR2 koff estimates and experimentally determined kinetic rates, we compare and interpret the receptor–ligand unbinding kinetics obtained using the newly reparameterized force fields for model host–guest systems and HSP90-inhibitor complexes. This method provides an opportunity to achieve higher accuracy in predicting receptor–ligand koff rate constants. Graphical representation of the partition of the phase-space of the receptor (grey)-ligand (yellow) complex into the MD region (further partitioned into Voronoi cells) and the BD region.
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影响因子：
2.9
作者：
Barros, TC;Stefaniak, K;Bohne, C
通讯作者：
Bohne, C
DOI：
10.1073/pnas.1907975116
发表时间：
2019-09-03
影响因子：
11.1
作者：
Bonati, Luigi;Zhang, Yue-Yu;Parrinello, Michele
通讯作者：
Parrinello, Michele
影响因子：
3.3
作者：
Cardenas, Alfredo E.;Elber, Ron
通讯作者：
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影响因子：
5.6
作者：
Ahn, Surl-Hee;Jagger, Benjamin R.;Amaro, Rommie E.
通讯作者：
Amaro, Rommie E.
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD