Conformational Analysis of the Loop-to-Helix Transition of the α‑Helix3 Plastic Region in the N‑Terminal Domain of Human Hsp90α by a Computational Biochemistry Approach

Hsp90 is a chaperone protein aiding
in correct protein folding
and attractive for drug discovery. The structure of human Hsp90α
N-terminal domain (NTD) is intriguing since the α-helix3 region
of the ATP-binding site in the NTD plastically changes its conformation,
i.e., loop-out, loop-in, and helical conformations, according to the
bound inhibitor type. The plastic region structure is known to influence
the mode of inhibition–inhibitors bound to a helix have a longer
residence time in the complex, which is a factor of in vivo-active
drugs, compared with loop binders. In this study, we analyzed the
loop-to-helix transition of the plastic region through binding of
a helix binder by a computational biochemistry approach. To generate
the helical transition from the loop, the resorcinol inhibitor C1
complexed with a loop-in structure was alchemically transformed to
the C10 inhibitor, which is known as a helix binder. The loop in the
C1 complex possesses Leu107 tightly binding to the hydrophobic subpocket,
considered as a key residue for the plasticity. From 10 × 1 μs
simulations after the alchemical transformation, the helical transition
was observed with a 29% success rate. Conformational analysis of the
simulations identified residues possibly associated with the helical
transition. The implementation of additional simulations (dihedral-constrained
and in silico mutant simulations) led to a statistically significant
increase in the transition success rate to 78%, as observed in Asn105
psi-constrained simulation. Therefore, we concluded that the Asn105
psi dihedral angle is most likely involved in the helical transition
by a change of the dihedral angle to gauche-negative.