A peptide’s perspective of water dynamics

Abstract

This Perspective is focused on amide groups of peptides interacting with water. The 2D IR spectroscopy has already enabled structural aspects of the peptide backbone to be determined through its ability to measure the coupling between different amide-I modes. Here we describe why nonlinear IR is emerging as the method of choice to examine the fast components of the water dynamics near peptides and how isotopically edited peptide links can be used to probe the local water at a residue level in proteins. This type of research necessarily involves an intimate mix of theory and experiment. The description of the results is underpinned by relatively well established quantum-statistical theories that describe the important manifestations of peptide vibrational frequency fluctuations.

2D IR spectroscopy reveals the role of water in the binding of channel-blocking drugs to the influenza M2 channel

“…Since that the forward and backward transfer rates are connected through the equilibrium constant, the rate k AB can be calculated from the fitted exchange rates, which is (0.6 ps) −1 , (1.9 ps) −1 , and (0.8 ps) −1 for the drug free, rimantadine bound, and spiran amine bound channels, respectively. Since experiments 47,51,55 and simulations 48 have revealed a timescale of ∼1 ps for hydrogen bond making and breaking for model amides in aqueous solution, these results are thus in accordance with the above mentioned idea that the doublet arises from different hydration/electrostatic states of the Ala30 amide in the same channel.…”

“…In bulk water, hydrogen bonds break and form on the timescale of ∼1 ps, which is reflected in the frequency correlation function of small solvated peptides. 47 The timescales measured here indicate that the drug increases the dynamics of the water in the channel, but the dynamics are still slower than in comparison to bulk water. The doublets observed for Gly34 and Ala30 at pH 5, however, make an accurate assessment of their spectral diffusion dynamics difficult, as it has been shown that for overlapping bands, the commonly used metrics, such as the center line slope, do not yield relaxation functions that represent the decay of the underlying frequency-frequency correlation function.…”

“…One noticeable difference between the spectra of Ala30 and Gly34 is that the Ala30 peak is blue-shifted by ∼5 cm −1 compared to the Gly34 band. Noting that backbone amide vibrational frequencies are susceptible to the electrostatic environment inside a protein, 30,47,48 the frequency difference between the Ala30 and the Gly34 bands is not unexpected, considering that the Ala30 residues are one turn further away from the charged His37 sidechains.…”

“…42,47 The decay of the frequencyfrequency correlation function is reflected in the evolution of the corresponding 2D spectral shape with the waiting time. However, 2D lineshapes are often dominated by homogeneous and inhomogeneous contributions, and the waiting time evolution of the lineshape is not always apparent and easily quantifiable, such as in the current case.…”

“…As shown in Figure 7, where the growth of the ratio of the cross peak to the diagonal peak at lower frequency is plotted, a cursory inspection suggests that the cross peaks obtained at all three experimental conditions exhibit a growth time of less than 2 ps, which is consistent with previous reports on amide spectral diffusion in aqueous solutions. 47,51 A detailed treatment of the third order responses that contribute to the 2D IR signal for such a system in equilibrium has been presented elsewhere. 61,62 For such a two-state equilibrium process, the ratio of the diagonal and cross-peak signals in the 2D spectrum can be used to isolate the rate constants and thus the timescales for the exchange process.…”