Redox-Driven Conformational Dynamics in a Photosystem-II-Inspired β-Hairpin Maquette Determined through Spectroscopy and Simulation

Abstract

Tyrosine-based radical transfer plays an important role in photosynthesis, respiration, and DNA synthesis. Radical transfer can occur either by electron transfer (ET) or proton coupled electron transfer (PCET), depending on the pH. Reversible conformational changes in the surrounding protein matrix may control reactivity of radical intermediates. De novo designed Peptide A is a synthetic 18 amino-acid β-hairpin, which contains a single tyrosine (Y5) and carries out a kinetically significant PCET reaction between Y5 and a cross-strand histidine (H14). In Peptide A, amide II' (CN) changes are observed in the UV resonance Raman (UVRR) spectrum, associated with tyrosine ET and PCET; these bands were attributed previously to a reversible change in secondary structure. Here, we use molecular dynamics simulations to define this conformational change in Peptide A and its H14-to-cyclohexylalanine variant, Peptide C. Three different Y5 charge states, tyrosine (YH), tyrosinate (Y), and neutral tyrosyl radical (Y·), are considered. The simulations show that Peptide A-YH and A-Y retain secondary structure and noncovalent interactions, whereas A-Y· is unstable. In contrast, both Peptide C-Y and Peptide C-Y· are unstable, due to the loss of the Y5-H14 π-π interaction. These simulations are consistent with previous UVRR experimental results on the two β-hairpins. Furthermore, they demonstrate the ability of simulations using fixed-charge force fields to accurately capture redox-linked conformational dynamics in a β-strand peptide.

Exploring Coupled Redox and pH Processes with a Force Field-Based Approach: Applications to Five Different Systems

“…We have concluded that the influence of the tyrosine state is minor in the unfolding process. For the record, it is important to mention that the tyrosine charges used by Hwang et al 27 match closely with ours for the OH and Ostates, however, significant discrepancies are observed for the •O state.…”

“…It is shifted down by approximately 193 mV at pH 13.4 in comparison to the standard redox potential of acetyl-Ltyrosinamide at the same pH 24 . The second maquette system is simply called peptide A (see Figure 1D) [26][27][28] . It is composed by a sequence of 18 amino acids, has a β-hairpin shape, and displays contacts between the side chains of a tyrosine and a histidine 26 .…”

Design and structural characterisation of monomeric water-soluble α-helix and β-hairpin peptides: State-of-the-art

“…β-Hairpin peptides have been shown to carry on proton-coupled electron transfer reactions between the side chains of cross-strand Tyr/His pairs [293][294][295][296] and between Tyr/Trp pairs [297].…”

Calcium, conformational selection, and redox-active tyrosine YZ in the photosynthetic oxygen-evolving cluster

“…Redox-coupled structural changes have been proposed to occur at two points in the RNR PCET pathway, Y122 and Y731 (43,46,47). In addition, redox-coupled changes in secondary structure have been observed and simulated in beta hairpin peptides (48). Thus, conformational gating could be a general method of targeting and controlling PCET pathways in enzymes.…”