Conformational preferences and pK_a value of selenocysteine residue

Abstract

The conformational preferences of the L-selenocysteine (Sec) dipeptides with selenol and selenolate groups (Ac-Sec-NHMe and Ac-Sec(-) -NHMe, respectively) and the apparent (i.e., macroscopic) pK(a) value of the Sec residue have been studied using the dispersion-corrected density functionals M06-2X and B2PLYP-D with the implicit solvation method in the gas phase and in water. In the gas phase, the backbone-to-backbone and/or side chain-to-backbone hydrogen bonds are found to contribute in stabilizing the most preferred conformations for the Sec and Sec(-) residues, as seen for the Cys and Cys(-) residues. However, the polyproline II-like conformations prevail over the conformations with the backbone-to-backbone hydrogen bonds in water because of the weakened hydrogen bonds by the favorable direct interactions between the backbone CO and HN groups and water molecules. The Sec and Sec(-) residues are found to adopt more various conformations than the Cys and Cys(-) residues in water, although the most preferred conformations of the neutral and/or anionic forms of the two residues are similar each other in the gas phase and in water. Using the statistically weighted free energies of the Sec and Sec(-) dipeptides in the gas phase and their solvation free energies, the pK(a) value of the Sec residue is estimated to be 5.47 at 25°C, which is in good agreement with the experimental value of 5.43 ± 0.02. It is found that the lower pK(a) value of the selenol side chain for the Sec residue by ∼3 units than the thiol side chain for the Cys residue is ascribed to the higher gas-phase acidity of the Sec residue.

Arylation Chemistry for Bioconjugation

“…[210] Selenols are much more nucleophilic than thiols mainly because of the greater polarizability of selenium compared to sulfur. [211] Moreover,a lkyl selenols are quite acidic (pK a % 5-7), [211] making the selenolate the dominant form of Sec at physiological pH. Both factors make Sec an appealing bioconjugation handle for site-selective protein modification with electrophiles such as maleimides.…”

Assessment of reagents for selenocysteine conjugation and the stability of selenocysteine adducts

“…23, 24 Compared to its cysteine counterpart (pKa = ~ 8), Sec has a lower pKa (~ 5) and enhanced nucleophilicity, which permits selective Sec conjugation in the presence of cysteines and other natural amino acids. 25 Based on this property, we have introduced a unique class of selenocysteine (Sec)-modified antibodies (SELENOMABS) that allow site-specific antibody modification leading to homogeneous ADCs. 26, 27 Furthermore, we demonstrated that SELENOMAB-oxadiazole conjugates had enhanced stability relative to maleimide counterparts.…”

Arylierungschemie für die Biokonjugation

“…[210] Selenole sind wesentlich nukleophiler als Thiole,w as auf die ausgeprägtere Polarisierbarkeit von Selen zurückgeht. [211] Außerdem sind Alkylselenole recht acide (pK a % 5-7), [211] weswegen Selenocystein bei physiologischem pH-Wert hauptsächlich in der Selenolatform vorliegt. Ausd iesen Gründen stellt Selenocystein einen vielversprechenden Ankerpunkt fürd ie regioselektive Proteinmodifikation mit Elektrophilen wie Maleimid dar.…”