Review Article Cite This: J. Phys. Chem. B XXXX, XXX, XXX−XXX
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Equilibrium versus Nonequilibrium Peptide Dynamics: Insights into Transient 2D IR Spectroscopy David G. Hogle, Amy R. Cunningham, and Matthew J. Tucker*
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Department of Chemistry, University of Nevada, Reno, 1664 North Virginia Street, Reno, Nevada 89557, United States ABSTRACT: Over the past two decades, two-dimensional infrared (2D IR) spectroscopy has evolved from the theoretical underpinnings of nonlinear spectroscopy as a means of investigating detailed molecular structure on an ultrafast time scale. The combined time and spectral resolution over which spectra can be collected on complex molecular systems has led to the precise structural resolution of dynamic species that have previously been impossible to directly observe through traditional methods. The adoption of 2D IR spectroscopy for the study of protein folding and peptide interactions has provided key details of how small changes in conformations can exert major influences on the activities of these complex molecular systems. Traditional 2D IR experiments are limited to molecules under equilibrium conditions, where small motions and fluctuations of these larger molecules often still lead to functionality. Utilizing techniques that allow the rapid initiation of chemical or structural changes in conjunction with 2D IR spectroscopy, i.e., transient 2D IR, a vast dynamic range becomes available to the spectroscopist uncovering structural content far from equilibrium. Furthermore, this allows the observation of reaction pathways of these macromolecules under quasi- and nonequilibrium conditions.
I. INTRODUCTION Traditionally, infrared spectroscopy has focused mainly on the identification of specific functional groups within a variety of molecular scaffolds. However, the advent of the twenty-first century has seen the reemergence of infrared spectroscopy as a tool of choice for analysis in nanotechnology, medicine, and biotechnology.1−3 Advances in materials science and theory have overcome several challenges to achieve the modern, structurally sensitive, time-dependent methods that have led to this resurgence in IR spectroscopy. New multidimensional nonlinear coherent spectroscopic techniques can resolve ambiguity in spectral features resulting from overlapping vibrational bands and convoluted line-broadening processes.4 Whereas one-dimensional methods project the molecular response of systems with many degrees of freedom onto a single frequency axis which makes detailed analysis difficult due to overlapping signals, multidimensional spectroscopies can disentangle the underlying molecular interactions using multiple light interactions. The molecular response, in the form of a vibrational echo, allows the system to be observed with significantly improved time and spatial resolution. Advances in optical technology have progressively led to more precise resolving power in the time domain, allowing for greater abilities in distinguishing spectral features.5 Although multidimensional methods, such as two-dimensional nuclear magnetic resonance (2D NMR) have been used for some time, infrared spectroscopy provides a means to apply similar approaches with faster time resolution to study molecules in anisotropic media,6,7 thus enabling a variety of applications in chemistry and biophysics. Prior to the development of two-dimensional infrared (2D IR) methods, X-ray crystallography and NMR measurements provided atomically resolved structures of a wide variety of © XXXX American Chemical Society
biomolecules. While these techniques resolved static structures to give important insights into biomolecular function, biomolecules undergo conformational changes and transient molecular interactions to perform various tasks and are therefore dynamic entities.8 Time-resolved X-ray crystallography remains technically challenging to apply on a broad scale,9,10 while 2D NMR captured many of these time-dependent structures but is typically hampered by the limitations of NMR methods in that they can only follow such structural changes on millisecond time scales.11 2D IR spectroscopy can resolve equilibrium processes on picosecond or faster time scales through either dynamics of conformational distributions or mapping vibrational coupling between molecular groups to obtain relative positions and orientations.12,13 For example, the initial movements that occur as an unfolded peptide chain transforms into a helix or sheet occur on an extremely fast time scale (under a nanosecond), yet they are instrumental in determining how the motif behaves relative to the larger structure.14 The complexity of the factors involved allows for numerous variations upon basic motifs, with small yet significant structural changes occurring on a variety of time scales ranging from the ultrafast to the ultraslow.15 This variety of possible motions causes extreme difficulties for accurate modeling on an atomic level, as these small fast motions may by instrumental in determining the subsequent folding pathway. Knowledge of these motions associated with the folding pathway provides insights into the possible misfolds that can occur, leading to disease. Oftentimes, it is these initial movements that Received: May 27, 2018 Revised: July 20, 2018 Published: July 24, 2018 A
DOI: 10.1021/acs.jpcb.8b05063 J. Phys. Chem. B XXXX, XXX, XXX−XXX
Review Article
The Journal of Physical Chemistry B are altered, leading to macroscopic changes in proteins resulting in some malfunction of the system. Thus, the insights provided about the folding pathway can lead to therapeutic treatments. Furthermore, knowing how secondary structures are affected by their environment from both intramolecular and solvent effects would allow the generation of algorithms with greater predictive power. The development and application of transient 2D IR methods in this area allows for the assessment of structures with sufficient molecular detail in a time-dependent manner and provides an avenue to push the limits of molecular dynamics simulations. Several challenges remain in understanding the behavior of proteins such as determining the relevant kinetic events and transition states in folding processes, as well as how proteins interact with membranes, hydrogen bonds, and dimer or higherorder oligomer formation. Transient two-dimensional infrared methods are well-suited to the study of quasi- or nonequilibrium states with high time resolution (
