Efficient Search for Energetically Favorable Molecular Conformations against Metastable States via Gray-Box Optimization

In order to accurately understand and estimate molecular properties, finding energetically favorable molecular conformations is the most fundamental task for atomistic computational research on molecules and materials. Geometry optimization based on quantum chemical calculations has enabled the conformation prediction of arbitrary molecules, including de novo ones. However, it is computationally expensive to perform geometry optimizations for enormous conformers. In this study, we introduce the gray-box optimization (GBO) framework, which enables optimal control over the entire geometry optimization process, among multiple conformers. Algorithms designed for GBO roughly estimate energetically preferable conformers during their geometry optimization iterations. They then preferentially compute promising conformers. To evaluate the performance of the GBO framework, we applied it to a test set consisting of seven dipeptides and mycophenolic acid to determine their stable conformations at the density functional theory level. We thus preferentially obtained energetically favorable conformations. Furthermore, the computational costs required to find the most stable conformation were significantly reduced (approximately 1% on average, compared to the naive approach for the dipeptides)