Computer simulation of molecular recognition in biomolecular system: from in silico screening to generalized ensembles

Biophys Rev. 2022 Nov 28;14(6):1423-1447. doi: 10.1007/s12551-022-01015-8. eCollection 2022 Dec.


Prediction of ligand-receptor complex structure is important in both the basic science and the industry such as drug discovery. We report various computation molecular docking methods: fundamental in silico (virtual) screening, ensemble docking, enhanced sampling (generalized ensemble) methods, and other methods to improve the accuracy of the complex structure. We explain not only the merits of these methods but also their limits of application and discuss some interaction terms which are not considered in the in silico methods. In silico screening and ensemble docking are useful when one focuses on obtaining the native complex structure (the most thermodynamically stable complex). Generalized ensemble method provides a free-energy landscape, which shows the distribution of the most stable complex structure and semi-stable ones in a conformational space. Also, barriers separating those stable structures are identified. A researcher should select one of the methods according to the research aim and depending on complexity of the molecular system to be studied.

Keywords: Conformation sampling; Drug discovery; Energy basin; Enhanced sampling; Free-energy landscape; Molecular binding; Thermodynamic integration; Weighted ensemble analysis method.

Publication types

  • Review