Interactions between Large Molecules: Puzzle for Reference Quantum-Mechanical Methods

TL;DR

This paper compares high-accuracy quantum-mechanical methods, CCSD(T) and DMC, for large molecular interactions, revealing significant discrepancies that challenge their reliability as benchmarks for complex systems.

Contribution

It demonstrates that CCSD(T) and DMC can disagree significantly on large, polarizable supramolecular interactions, highlighting limitations in current benchmark methods.

Findings

Discrepancies up to 8 kcal/mol in interaction energies.

Differences of up to 6 orders of magnitude in binding constants.

Inconsistencies challenge the assumption of agreement between methods.

Abstract

Quantum-mechanical methods are widely used for understanding molecular interactions throughout biology, chemistry, and materials science. Quantum diffusion Monte Carlo (DMC) and coupled cluster with single, double, and perturbative triple excitations [CCSD(T)] are two state-of-the-art and trusted wavefunction methods that have been categorically shown to yield accurate interaction energies for small organic molecules. These methods provide valuable reference information for widely-used semi-empirical and machine learning potentials, especially where experimental information is scarce. However, agreement for systems beyond small molecules is a crucial remaining milestone for cementing the benchmark accuracy of these methods. Approaching such well-converged predictive power in larger molecules has motivated major developments in CCSD(T) as well as DMC algorithms in the past years, resulting in orders of magnitude time-to-solution reductions. Here, we show that CCSD(T) and DMC interaction energies are not in consistent agreement for a set of polarizable supramolecules. Whilst agreement is found for some of the complexes, in a few key systems disagreements of up to 8 kcal/mol remained. This leads to differences of up to 6 orders of magnitude in the corresponding binding association constant at room temperature for systems which are well within the accustomed domain of applicability for both methods. These findings thus indicate that more caution is required when aiming at reproducible non-covalent interactions between extended molecules. Our data contradicts the expectation that the most comprehensive and robust wavefunction methods predict identical non-covalent interactions and indicate an unsolved challenge for benchmark approaches.