Search

International audience; Molecular assembly and reactivity have been investigated with a series of 3H-1,2-benzodithiol-3-(thi)one derivatives and their (mixed) selenated analogs. Electrostatic potential calculations on monomers show three σ-hole regions around the dichalcogenide Ch-Ch bond (Ch = S, Se), one side-on and two along the bonding direction. The topological analysis of the electron density ρ(r) points to the weak nature of the Ch-Ch bond. σ-Hole and lone-pair regions are described in terms of charge depletion (CD) and charge concentration (CC) sites found in the valence shell of chalcogen atoms. Whereas CD and CC sites are characterized by the topological critical points of L(r) = -2ρ(r), their electrophilic and nucleophilic powers are measured by the corresponding L/ρ magnitudes. In crystal structures, each chalcogen bond (ChB) involves a σ-hole region and shows a CD⋯CC interaction that aligns with the internuclear direction of the atoms the CD and CC sites belong. The alignment holds simultaneously for all of the ChB interactions in each crystal structure, indicating that CD⋯CC interactions drive molecular orientation in molecular assembly. Strength of ChB is measured in terms of the topological properties of ρ(r), whereas the intensity of the electrophilic⋯nucleophilic interaction is monitored by [(L/ρ)CC - (L/ρ)CD]/dCC⋯CD2. The σ-hole in side-on conformation forms the strongest ChB interactions in molecular assembly. Reactivity of molecules against nucleophilic attack has been investigated along each of the three σ-hole regions by using fluoride as a probe. Adducts formed along the Ch-Ch bonding direction are energetically more favorable than in side-on conformation. At optimized geometries, the F⋯Ch bond (Ch = S, Se) exhibits a partial covalent character, while it weakens concomitantly the Ch⋯Ch bond that also becomes of partial covalent character. In the reactivity process, the significant reorientation of the plane containing the chalcogen lone pairs, along with the opening, shrinking, and splitting of reactivity surfaces 2ρ(r) = 0, is the signature of the charge redistribution that involves the nucleophilic attack. © 2020 American Chemical Society.

Protein C (PC) is a key regulator of blood clotting and inflammation. Its inherited deficiency is associated with venous thromboembolism, and recombinant activated PC is currently used to increase survival in severe sepsis. The molecular basis of inherited PC deficiency is heterogeneous. Due to its multiple physiologic interactions and functions, and its modular structure, natural variants aid in the understanding of the relationship between critical residues and discrete functions. This knowledge has important therapeutic implications in the planning of a recombinant activated PC with a specific therapeutic target and devoid of major collateral effects. A way of predicting important functional consequences of residue variation is the use of molecular modeling and structural interpretation of amino acidic substitutions. A study of 21 out of 32 identified PC gene (PROC) variants is presented. For three of them, localized in the active site, electrostatic potential variation was calculated. For more than half of the studied variants, an explanation for the functional impairment could be derived from computational analysis, allowing a focused choice of which variants it is worthwhile pursuing. Hum Mutat 28(4), 345–355, 2007. © 2006 Wiley-Liss, Inc.