Quick-and-Easy Validation of Protein–Ligand Binding Models Using Fragment-Based Semiempirical Quantum Chemistry

片段(逻辑) 趋同(经济学) 电子结构 计算机科学 量子 先验与后验 蛋白质配体 计算化学 化学 配体(生物化学) 统计物理学 算法 物理 量子力学 受体 生物化学 有机化学 哲学 认识论 经济 经济增长
作者
Paige Bowling,Dustin Broderick,John M. Herbert
出处
期刊:Journal of Chemical Information and Modeling [American Chemical Society]
标识
DOI:10.1021/acs.jcim.4c01987
摘要

Electronic structure calculations in enzymes converge very slowly with respect to the size of the model region that is described using quantum mechanics (QM), requiring hundreds of atoms to obtain converged results and exhibiting substantial sensitivity (at least in smaller models) to which amino acids are included in the QM region. As such, there is considerable interest in developing automated procedures to construct a QM model region based on well-defined criteria. However, testing such procedures is burdensome due to the cost of large-scale electronic structure calculations. Here, we show that semiempirical methods can be used as alternatives to density functional theory (DFT) to assess convergence in sequences of models generated by various automated protocols. The cost of these convergence tests is reduced even further by means of a many-body expansion. We use this approach to examine convergence (with respect to model size) of protein–ligand binding energies. Fragment-based semiempirical calculations afford well-converged interaction energies in a tiny fraction of the cost required for DFT calculations. Two-body interactions between the ligand and single-residue amino acid fragments afford a low-cost way to construct a "QM-informed" enzyme model of reduced size, furnishing an automatable active-site model-building procedure. This provides a streamlined, user-friendly approach for constructing ligand binding-site models that requires neither a priori information nor manual adjustments. Extension to model-building for thermochemical calculations should be straightforward.
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