Influence of serine in position i on conformation and dynamics of reverse turns

NMR spectroscopy has been employed for the conformational analysis of the cyclic hexapeptide cycle(‐d‐Pro¹‐Ala²‐Ser³(Bzl)‐Trp⁴‐Orn⁵(Z)‐Tyr⁶‐) with and without protecting groups on Ser³ and Orn⁵. This peptide sequence was derived from the active loop sequence of the α‐amylase inhibitor Tendamistat (HOE 467). The aim was to investigate the role of serine in position i of a standard β‐turn on the conformation and stabilization of this turn. Based on distance and torsion constraints from 2D NMR spectroscopic measurements in DMSO‐d₆ solution, structure refinement was accomplished by restrained molecular dynamics (MD) simulations in vacuo and in DMSO. The analysis of both structures in solution reveals a considerable effect of the unprotected serine sidechain on the adjacent β‐turn conformation. While in the protected peptide with Ser³(Bzl) a βII‐turn is observed between Trp⁴ and Orn⁵, the deprotected compound reveals a βI‐turn in this region. The βI‐turn is stabilized by a backbone‐sidechain hydrogen bond from Orn⁵N_αH to Ser³O_γ. Comparisons with other NMR‐derived solution structures of cyclic model peptides and in some protein structures from literature reveal a general structural motif in the stabilization of βI‐turns by serine in the i position through backbone‐sidechain interactions. © Munksgaard 1995.