We report the density functional theory (DFT) guided discovery of ethynyl-triazolyl-phosphinates (ETPs) as a new class of electrophilic warheads for cysteine selective bioconjugation. By using Cu I -catalysed azide alkyne cycloaddition (CuAAC) in aqueous buffer, we were able to access a variety of functional electrophilic building blocks, including proteins, from diethynyl-phosphinate. ETP-reagents were used to obtain fluorescent peptide-conjugates for receptor labelling on live cells and a stable and a biologically active antibodydrug-conjugate. Moreover, we were able to incorporate ETP-electrophiles into an azide-containing ubiquitin under native conditions and demonstrate their potential in protein-protein conjugation. Finally, we showcase the excellent cysteine-selectivity of this new class of electrophile in mass spectrometry based, proteome-wide cysteine profiling, underscoring the applicability in homogeneous bioconjugation strategies to connect two complex biomolecules.
We employed the chemical potential equalization principle to demonstrate that fractional electrons are involved in the electro-inductive effect as well as the vibrational Stark effect. By the chemical potential model, we were able to deduce that the frontier molecular orbitals of immobilized molecules can provide valuable insight into these effects. To further understand and quantify these findings, we introduced fractional charge density functional theory (FC-DFT), a canonical ensemble approach for open systems. This method allows for the calculation of electronic energies, nuclear gradients, and the Hessian matrix of fractional electronic systems. To correct the spurious delocalization error commonly found in approximate density functionals for small systems, we imposed the Perdew−Parr−Levy−Balduz (PPLB) condition through linear interpolation of two adjacent integer points (LI-FC-DFT). Although this approach is relatively simple in terms of molecular modeling, the results obtained through LI-FC-DFT calculations predict the same trend seen in experimental reactivity and the frequency change of immobilized molecules.
We employed the chemical potential neutralization principle to demonstrate that fractional electrons are involved in the electro-inductive effect as well as the vibrational Stark effect. By the chemical potential model, we were able to deduce that the frontier molecular orbitals of immobilized molecules can provide valuable insight into these effects. To further understand and quantify these findings, we introduced fractional charge density functional theory (FC-DFT), a canonical ensemble approach for open systems. This method allows for the calculation of electronic energies, nuclear gradients, and the Hessian matrix of fractional electronic systems. To correct the spurious delocalization error commonly found in approximate density functionals for small systems, we imposed the Perdew-Parr-Levy-Balduz (PPLB) condition through linear interpolation of two adjacent integer points (LI-FC-DFT). Although this approach is relatively simple in terms of molecular modeling, the results obtained through LI-FC-DFT calculations predict the same trend seen in experimental reactivity and the frequency change of immobilized molecules.
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