Interstitial or interstitialcy: effect of the cation size on the migration mechanism in NaSICON materials.

Sodium superionic conductors (NaSICONs) with general formula NaM2A3O12 have attracted significant attention as solid electrolytes for all solid-state batteries owing to their remarkable room temperature ionic conductivity in the order of 10-3 S cm-1. Their flexible structural framework, which allows the incorporation of various aliovalent cations, affects the Na+ ion transport. However, establishing a straightforward correlation between Na+ mobility and NaSICON composition proves challenging due to competing influences such as framework alteration and stoichiometric changes of the cation substituents and thus the mobile Na+ ions. Therefore, we systematically investigate the NaSICON system across various Na1+xM2SixP3-xO12 compositions. We unravel and examine independently two key aspects impacting the Na+ ion transport in NaSICONs: structural factors determined by introduced M4+ framework cations and the substitution level (x). By employing DFT calculations, we explore the interstitial- and interstitialcy-like migration mechanisms, revealing that these mechanisms and the associated migration energies are primarily influenced by metastable transient states traversed during the Na+ ion migration. The stability of these transient states, in turn, depends on the spatial arrangement of the Na+ ions, the size of the M4+ cations defining the structural framework, and x. This study enhances our fundamental understanding of Na+ ion migration within NaSICONs across a wide range of compositions. The findings offer valuable insights into the microscopic aspects of NaSICON materials and provide essential guidance for prospective studies in this field.

Pomotrelvir and Nirmatrelvir Binding and Reactivity with SARS-CoV-2 Main Protease: Implications for Resistance Mechanisms from Computations.

We investigate the inhibition mechanism between pomotrelvir and the SARS-CoV-2 main protease using molecular mechanics and quantum mechanics/molecular mechanics simulations. Alchemical transformations where each Pi group of pomotrelvir was transformed into its counterpart in nirmatrelvir were performed to unravel the individual contribution of each group to the binding and reaction processes. We have shown that while a γ-lactam ring is preferred at position P1, a δ-lactam ring is a good alternative for the design of inhibitors for variants presenting mutations at position 166. For the P2 position, tertiary amines are preferred with respect to secondary amines. Flexible side chains at the P2 position can disrupt the preorganization of the active site, favouring the exploration of non-reactive conformations. The substitution of the P2 group of pomotrelvir by that of nirmatrelvir resulted in a compound, named as C2, that presents a better binding free energy and a higher population of reactive conformations in the Michaelis complex. Analysis of the chemical reaction to form the covalent complex has shown a similar reaction mechanism and activation free energies for pomotrelvir, nirmatrelvir and C2. We hope that these findings could be useful to design better inhibitors to fight present and future variants of the SARS-CoV-2 virus.