Comparative Analysis of Quantum-Mechanical and Standard Single-Structure Protein–Ligand Scoring Functions with MD-Based Free Energy Calculations
Year: 2025
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide Single-structure scoring functions have been considered inferior to expensive ensemble free energy methods in predicting protein–ligand affinities. We are revisiting this dogma with the recently developed semiempirical quantum-mechanical (SQM)-based scoring function, SQM2.20, comparing its performance to the standard scoring functions on one hand and state-of-the-art molecular dynamics (MD)-based free-energy methods on the other hand. The comparison is conducted on a well-established Wang data set comprising eight protein targets with 200 ligands. The initial low correlation of SQM2.20 scores with the experimental binding affinities of R 2 = 0.21 was improved to R 2 = 0.47 by a systematic refinement of the input structures and omission of the ligand deformation energy. Consequently, SQM2.20 representing accurate single-structure scoring functions, exhibited an average performance comparable to that of MD-based methods ( R 2 = 0.52) and surpassed the performance of standard scoring functions ( R 2 = 0.26). The per-target analysis highlighted the pivotal role of high-quality input structures on the outcomes of single-structure methods. In the instances where such structures are available, SQM2.20 scoring has been shown to rival or even exceed MD-based methods in predicting protein–ligand binding affinities, while exhibiting significantly reduced computation time.
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Award: G1761812275
OpenAlex ID: W4412522319