Intrinsic folding of the cysteine residue: competition between folded and extended forms mediated by the –SH group

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A dual microwave and optical spectroscopic study of a capped cysteine amino acid isolated in a supersonic expansion, combined with quantum chemistry modelling, enabled us to characterize the conformational preferences of Cys embedded in a protein chain. IR/UV double resonance spectroscopy provided evidence for the coexistence of two conformers, assigned to folded and extended backbones (with classical C7 and C5 backbone H-bonding respectively), each of them additionally stabilized by specific main-chain/side-chain H-bonding, where the sulfur atom essentially plays the role of H-bond acceptor. The folded structure was confirmed by microwave spectroscopy, which demonstrated the validity of the DFT-D methods currently used in the field. These structural and spectroscopic results, complemented by a theoretical Natural Bond Orbital analysis, enabled us to document the capacity of the weakly polar-CH2-SH side chain of Cys to adapt itself to the intrinsic local preferences of the peptide backbone, i.e., a γ-turn or a β-sheet extended secondary structure. The corresponding local H-bonding bridges the side chain acceptor S atom to the backbone NH donor site of the same or the next residue along the chain, through a 5-or a 6-membered ring respectively.
Support from the French National Research Agency (ANR; Grant ANR-17-CE29-0008 ‘‘TUNIFOLD-S’’) and from the ‘‘Investissements d’Avenir’’ Funding program (LabEx PALM; grant ANR-10-LABX-0039-PALM; DIRCOS) are acknowledged. This work was granted access to the HPC facility of [TGCC/CINES/ IDRIS] under the Grant 2019-A0050807540 awarded by GENCI (Grand Equipement National de Calcul Intensif) and to the CCRT High Performance Computing (HPC) facility at CEA under the Grant CCRT2019-p606bren. We also acknowledge the use of the computing facility cluster Me´soLUM of the LUMAT federation (FR LUMAT 2764). The financial fundings from Ministerio de Ciencia e Innovacion (CTQ2016-76393-P), Junta de Castilla y Leon (Grant VA077U16) and the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC-2013-SyG, Grant Agreement no. 610256 NANOCOSMOS, are gratefully acknowledged.