Atomistic modeling has by now become an integral part of technological and pharmacological developments. In such nanoscale applications, non-covalent interactions — including electrostatics, induction, and van der Waals (vdW) dispersion — are paramount for the structure, stability, and dynamics of the relevant molecular systems and materials. The theoretical and computational description of non-covalent interactions in large-scale systems thereby relies on a variety of approximations such as a point-to-point-like electronic response, the pairwise additivity of vdW interactions, or the neglect of higher-order effects like the interplay of individual contributions. These common assumptions, while validated for small molecules, remain yet to be proven adequate for systems of increased size and complexity.
Here, we go beyond the above approximations and scrutinize their validity in nanoscale systems. The presented developments enable the description and analysis of non-local electronic response, the range of vdW forces, and higher-order non-covalent interactions. This allows to show the heterogeneous character of electronic response, provide new insights into the characteristics of van der Waals dispersion in solvated biomolecules, and highlight the role of so-far neglected contributions to the intermolecular interaction in realistic systems. For example, a quantum-mechanical many-body treatment of vdW dispersion reveals the importance of beyond-pairwise vdW interactions in the context of protein folding [Sci Adv 5, eaax0024 (2019)] and higher-order interactions, while indeed negligible for small molecules, can lead to qualitative changes to intermolecular forces within nanostructured environments [Nat Commun 12, 137 (2021)]. Overall, this talk highlights the complex scaling of non-covalent interactions and underlines the necessity of efficient quantum-mechanical methods in order to achieve a reliable description and understanding of practically-relevant systems.
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