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A semi-empirical counterpoise-type correction for basis set superposition error (BSSE) in molecular systems is presented. An atom pair-wise potential corrects for the inter- and intra-molecular BSSE in supermolecular Hartree-Fock (HF) or density functional theory (DFT) calculations. This geometrical counterpoise (gCP) denoted scheme depends only on the molecular geometry, i.e., no input from the electronic wave-function is required and hence is applicable to molecules with ten thousands of atoms. The four necessary parameters have been determined by a fit to standard Boys and Bernadi counterpoise corrections for Hobza's S66×8 set of non-covalently bound complexes (528 data points). The method's target are small basis sets (e.g., minimal, split-valence, 6-31G*), but reliable results are also obtained for larger triple-ζ sets. The intermolecular BSSE is calculated by gCP within a typical error of 10%-30% that proves sufficient in many practical applications. The approach is suggested as a quantitative correction in production work and can also be routinely applied to estimate the magnitude of the BSSE beforehand. The applicability for biomolecules as the primary target is tested for the crambin protein, where gCP removes intramolecular BSSE effectively and yields conformational energies comparable to def2-TZVP basis results. Good mutual agreement is also found with Jensen's ACP(4) scheme, estimating the intramolecular BSSE in the phenylalanine-glycine-phenylalanine tripeptide, for which also a relaxed rotational energy profile is presented. A variety of minimal and double-ζ basis sets combined with gCP and the dispersion corrections DFT-D3 and DFT-NL are successfully benchmarked on the S22 and S66 sets of non-covalent interactions. Outstanding performance with a mean absolute deviation (MAD) of 0.51 kcal/mol (0.38 kcal/mol after D3-refit) is obtained at the gCP-corrected HF-D3/(minimal basis) level for the S66 benchmark. The gCP-corrected B3LYP-D3/6-31G* model chemistry yields MAD=0.68 kcal/mol, which represents a huge improvement over plain B3LYP/6-31G* (MAD=2.3 kcal/mol). Application of gCP-corrected B97-D3 and HF-D3 on a set of large protein-ligand complexes prove the robustness of the method. Analytical gCP gradients make optimizations of large systems feasible with small basis sets, as demonstrated for the inter-ring distances of 9-helicene and most of the complexes in Hobza's S22 test set. The method is implemented in a freely available FORTRAN program obtainable from the author's website. [ABSTRACT FROM AUTHOR]

Cryo-EM and X-ray crystallography provide crucial experimental data for obtaining atomic-detail models of biomacromolecules. Refining these models relies on library-based stereochemical restraints, which, in addition to being limited to known chemical entities, do not include meaningful noncovalent interactions relying solely on nonbonded repulsions. Quantum mechanical (QM) calculations could alleviate these issues but are too expensive for large molecules. We present a novel AI-enabled Quantum Refinement (AQuaRef) based on AIMNet2 neural network potential mimicking QM at substantially lower computational costs. By refining 41 cryo-EM and 30 X-ray structures, we show that this approach yields atomic models with superior geometric quality compared to standard techniques, while maintaining an equal or better fit to experimental data., Competing Interests: Competing Interests The authors declare no competing interests.

Pseudouridine is the most frequently naturally occurring RNA modification, found in all classes of biologically functional RNAs. Compared to uridine, pseudouridine contains an additional hydrogen bond donor group and is therefore widely regarded as a structure stabilizing modification. However, the effects of pseudouridine modifications on the structure and dynamics of RNAs have so far only been investigated in a limited number of different structural contexts. Here, we introduced pseudouridine modifications into the U-turn motif and the adjacent U:U closing base pair of the neomycin-sensing riboswitch (NSR)-an extensively characterized model system for RNA structure, ligand binding, and dynamics. We show that the effects of replacing specific uridines with pseudouridines on RNA dynamics crucially depend on the exact location of the replacement site and can range from destabilizing to locally or even globally stabilizing. By using a combination of NMR spectroscopy, MD simulations and QM calculations, we rationalize the observed effects on a structural and dynamical level. Our results will help to better understand and predict the consequences of pseudouridine modifications on the structure and function of biologically important RNAs., (© 2023 Vögele et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Current interest in lone-pair⋅⋅⋅π (lp⋅⋅⋅π) interactions is gaining momentum in biochemistry and (supramolecular) chemistry. However, the physicochemical origin of the exceptionally short (ca. 2.8 Å) oxygen-to-nucleobase plane distances observed in prototypical Z-DNA CpG steps remains unclear. High-level quantum mechanical calculations, including SAPT2+3 interaction energy decompositions, demonstrate that lp⋅⋅⋅π contacts do not result from n→π* orbital overlaps but from weak dispersion and electrostatic interactions combined with stereochemical effects imposed by the locally strained structural context. They also suggest that the carbon van der Waals (vdW) radii, originally derived for sp 3 carbons, should not be used for smaller sp 2 carbons attached to electron-withdrawing groups. Using a more adapted carbon vdW radius results in these lp⋅⋅⋅π contacts being no longer of the sub-vdW type. These findings challenge the whole lp⋅⋅⋅π concept that refers to elusive orbital interactions that fail to explain short interatomic contact distances., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)