Predicting and Understanding Non-Covalent Interactions Using Novel Forms of Symmetry-Adapted Perturbation Theory

CONSPECTUS: Although sometimes derided as "weak" interactions, non-covalent forces play a critical role in ligand binding and crystal packing and in determining the conformational landscape of flexible molecules. Symmetry-adapted perturbation theory (SAPT) provides a framework for accurate ab initio calculation of intermolecular interactions and furnishes a natural decomposition of the interaction energy into physically meaningful components: semiclassical electrostatics (rigorously obtained from monomer charge densities), Pauli or steric repulsion, induction (including both polarization and charge transfer), and dispersion. This decomposition helps to foster deeper understanding of non-covalent interactions and can be used to construct transferable, physics-based force fields. Separability of the SAPT interaction energy also provides the flexibility to construct composite methods, a feature that we exploit to improve the description of dispersion interactions. These are challenging to describe accurately because they arise from nonlocal electron correlation effects that appear for the first time at second order in perturbation theory but are not quantitatively described at that level. As with all quantum-chemical methods, a major limitation of SAPT is nonlinear scaling of the computational cost with respect to system size. This cost can be significantly mitigated using "SAPT0(KS)", which incorporates monomer electron correlation by means of Kohn-Sham (KS) molecular orbitals from density functional theory (DFT), as well as by an "extended" theory called XSAPT, developed by the authors. XSAPT generalizes traditional dimer SAPT to many-body systems, so that a ligand-protein interaction (for example) can be separated into contributions from individual amino acids, reducing the cost of the calculation below that of even supramolecular DFT while retaining the accuracy of high-level ab initio quantum chemistry. This Account provides an overview of the SAPT0(KS) approach and the XSAPT family of methods. Several low-cost variants are described that provide accuracy approaching that of the best ab initio benchmarks yet are affordable enough to tackle ligand-protein binding and sizable host-guest complexes. These variants include SAPT+aiD, which uses ab initio atom-atom dispersion potentials ("+aiD") in place of second-order SAPT dispersion, and also SAPT+MBD, which incorporates many-body dispersion (MBD) effects that are important in the description of nanoscale materials. Applications to drug binding highlight the size-extensive nature of dispersion, which is not a weak interaction in large systems. Other applications highlight how a physics-based analysis can sometimes upend conventional wisdom regarding intermolecular forces. In particular, careful reconsideration of p-p interactions makes clear that the quadrupolar electrostatics (or "Hunter-Sanders") model of pi-pi stacking should be replaced by a "van der Waals model" in which conformational preferences arise from a competition between dispersion and Pauli repulsion. Our analysis also suggests that molecular shape, rather than aromaticity per se, is the key factor driving strong stacking interactions. Looking forward, we anticipate that XSAPT-based methods can play a role in screening of drug candidates and in materials design.