On the Quest of Dioxygen by Monomeric Sarcosine Oxidase. A Molecular Dynamics Investigation

It is reported here on random acceleration molecular dynamics (RAMD) simulations with the 2GF3 bacterial monomeric sarcosine oxidase (MSOX), O₂, and furoic acid in place of sarcosine, solvated by TIP3 H₂O in a periodic box. An external tiny force, acting randomly on O₂, accelerated its relocation, from the center of activation between residue K265 and the si face of the flavin ring of the flavin adenine dinucleotide cofactor, to the surrounding solvent. Only three of the four O₂ gates previously described for this system along a composite method technique were identified, while two more major O₂ gates were found. The RAMD simulations also revealed that the same gate can be reached by O₂ along different pathways, often involving traps for O₂. Both the residence time of O₂ in the traps, and the total trajectory time for O₂ getting to the solvent, could be evaluated. The new quick pathways discovered here suggest that O₂ exploits all nearby interstices created by the thermal fluctuations of the protein, not having necessarily to look for the permanent large channel used for uptake of the FADH cofactor. To this regard, MSOX resembles closely KijD3 N‐oxygenase. These observations solicit experimental substantiation, in a long term aim at discovering whether gates and pathways for the small gaseous ligands inside the proteins are under Darwinian functional evolution or merely stochastic control operates.