Establishing the accuracy of density functional approaches for the description of noncovalent interactions in biomolecules

Abstract

Biomolecules have complex structures, and noncovalent interactions are crucial to determine their conformations and functionalities. It is therefore critical to be able to describe them in an accurate but efficient manner in these systems. In this context density functional theory (DFT) could provide a powerful tool to simulate biological matter either directly for relatively simple systems or coupled with classical simulations like the QM/MM (quantum mechanics/molecular mechanics) approach. Additionally, DFT could play a fundamental role to fit the parameters of classical force fields or to train machine learning potentials to perform large scale molecular dynamics simulations of biological systems. Yet, local or semi-local approximations used in DFT cannot describe van der Waals (vdW) interactions, one of the essential noncovalent interactions in biomolecules, since they lack a proper description of long range correlation effects. However, many efficient and reasonably accurate methods are now available for the description of van der Waals interactions within DFT. In this work, we establish the accuracy of several state-of-the-art vdW-aware functionals by considering 275 biomolecules including interacting DNA and RNA bases, peptides and biological inhibitors and compare our results for the energy with highly accurate wavefunction based calculations. Most methods considered here can achieve close to predictive accuracy. In particular, the non-local vdW-DF2 functional is revealed to be the best performer for biomolecules, while among the vdW-corrected DFT methods, uMBD is also recommended as a less accurate but faster alternative.