The PBE+MBD interaction energy for indinavir@HIV is missing from Fig. due to convergence problems that warrant discussion. Molecular electronic structure calculations using atom- centered Gaussian basis functions typically employ diagonalization-based SCF solvers rather than minimization-based solvers, as the former are generally more efficient when direct diagonalization is feasible. In our experience, however, this is problematic for GGA calculations in large systems, especially in high-quality basis sets and in the presence of anionic functional groups. Ironically, we often find that a good way to converge a "low-cost" GGA calculation is to use a more expensive hybrid functional to generate a guess, as this tends to open up the HOMO/LUMO gap, but this did not work for PBE+MBD applied to indinavir@HIV. Severe convergence problems engendered by vanishing HOMO/LUMO gaps have also been noted when GGAs are applied to ionic liquids and proteins. Some have suggested that these difficulties are artifacts of vacuum boundary conditions, as convergence problems are often mitigated by means of dielectric boundary conditions. (A classical point-charge environment may also help. ) That said, hybrid functionals typically alleviate convergence problems, even in the presence of vacuum boundary conditions, suggesting that GGAs are not altogether innocent in this regard. In our view, the issue is artificial charge delocalization due to self-interaction error, which is especially severe in systems containing anionic moieties. Minimization-based solvers may avoid this problem by finding a local minimum that localizes charge, 328 whereas diagonalization-based solvers afford the (delocalized) global minimum, leading to charge sloshing during the SCF iterations. In summary, DFT errors across nanoscale vdW complexes are highly varied, with few discernible systematic trends toward over-or underbinding behavior. This much can be stated even without resolving the issue of whether FN-DMC or local-orbital CCSD(T) provides the more reliable benchmark in the not-infrequent cases where the two disagree for large systems. However that question may ultimately be resolved, it is sobering to realize that DFT calculations in larger noncovalent systems do not afford the same level of accuracy that one can now expect from DFT for noncovalent interaction energies in small vdW complexes. It is true that the interaction energies are simply larger in these larger systems, with |E int | ranging up to 42 kcal/mol for the systems in Fig. , according to LNO-CCSD(T)/CBS calculations, and from 21-122 kcal/mol for the systems in Fig. , according to DLPNO-CCSD(T 0 )/CBS calculations. For comparison, the S66 interaction energies range up to |E int | = 19 kcal/mol, but many of them are much smaller. The largest systems considered here represent the present frontier for first-principles description of vdW interactions, where results with contemporary dispersion-aware DFT methods are promising but not yet quantitative.