Structural change of retinoic-acid receptor-related orphan receptor induced by binding of inverse-agonist: Molecular dynamics and ab initio molecular orbital simulations.

To elucidate structural changes in the retinoic acid receptor-related orphan receptor gamma (RORγt) induced by the binding of an agonist or an inverse agonist, we conducted molecular dynamics (MD) simulations in explicit water. In addition, ab initio fragment molecular orbital calculations were carried out for certain characteristic structures obtained from the MD simulations to reveal important interactions between the amino acid residues of RORγt, and to distinguish the different effects in the binding of an agonist and an inverse agonist on the structure of RORγt. The results elucidate that the hydrogen bond between His479 of helix11 (H11) and Tyr502 of helix12 (H12) is important to keep the H12 conformation in the agonist-bound RORγt. In contrast, in the inverse-agonist-bound RORγt, the side chain of His479 rotates, significantly weakening the interaction between His479 and Tyr502, leading to a conformational change in H12. Therefore, the present molecular simulations clearly indicate that the conformational change in the side chain of His479 in the inverse-agonist-bound RORγt is the main reason for the H12 destabilization induced by the binding of the inverse agonist. Such a conformational change does not occur on the binding of the agonist in RORγt, owing to the strong hydrogen bond between His479 and Tyr502.

Protonation states of central amino acids in a zinc metalloprotease complexed with inhibitor: Molecular mechanics optimizations and ab initio molecular orbital calculations.

The zinc-metalloprotease pseudolysin (PLN) secreted from bacteria degrades extracellular proteins to produce bacterial nutrition. Since PLN has a Zn ion at the inhibitor-binding site, the interactions between Zn and PLN residues as well as inhibitor can be significantly changed depending on the protonation states of PLN residues at the inhibitor-binding site. To determine stable protonation states of these residues, we here considered different protonation states for Glu and His residues located around Zn and investigated the electronic states of the PLN + inhibitor complex, using ab initio molecular simulations. The protonation state of His223 was found to significantly affect the specific interactions between PLN and the inhibitor.