Recently, we have found that a simple lattice model can offer insight into the interpretation of both linear and two-dimensional IR (2D IR) experiments applied to study DNA oligonucleotide dehybridization. Turning to simplified models based on empirical results offers one route forward. As a result, the line shapes, intensities, and frequencies of these IR transitions are sensitive base-specific reporters of nucleic acid structure and, when tracked in time, base pairing dynamics. –1800 cm −1 range contains in-plane nucleobase modes and carbonyl stretches that are particularly useful for studying nucleic acid folding since the same physical interactions that mediate hybridization, namely, hydrogen bonding and base stacking, are also largely responsible for shaping the infrared spectrum in this region. Across the mid-IR, characteristic frequency ranges report on the sugar conformation, phosphate backbone orientation, glycosidic bond geometry, and the vibrations of the nucleobases themselves. 33,34 The toolbox of IR methods offers label-free structural information, and time-resolved IR spectroscopy can access dynamics down to the picosecond time scale. As a result, simple statistical models that can help explain experimental results in detail beyond the simplest all-or-none picture, but that lack finer detail and complexity, serve an important role.Īmong experimental methods, we and others have found infrared (IR) spectroscopy to be a valuable technique in the study of nucleic acid structure, 27–29 hydration, 30,31 folding dynamics, 8,9,32 and energy relaxation. Molecular dynamics (MD) simulations are capable of modeling the finest details of hybridization, 24–26 but relating simulated folding trajectories to experimental observables is nontrivial and running high-level MD simulations can present challenges to nonspecialists. Although this assumption is useful and adequate in many contexts, it has long been recognized that the all-or-none description is an oversimplification that offers little insight into the underlying molecular mechanism. Regardless of the experimental observable, the simplest and most widely applied model of hybridization thermodynamics and kinetics invokes the so-called all-or-none picture, in which all possible base pairs in a duplex are assumed fully intact and the transition to the single-strand state is marked by a concerted loss of all base pairing contacts. These methods include electronic 1–6 and vibrational spectroscopies, 7–9 nuclear magnetic resonance (NMR), 10–12 fluorescence-based measurements, 13–17 calorimetry, 18–20 and single molecule optical tweezers 21–23 to name a few. The thermodynamics and kinetics of nucleic acid folding have been studied over several decades using a wide variety of experimental techniques that offer complementary information about the hybridization process. The model captures the interplay between configurational variation and the enthalpic stabilization of base pairing contacts in the context of a minimalist statistical description of DNA hybridization and offers useful insight beyond the simplest all-or-none picture. Calculated free energy surfaces offer insight into the interpretation of temperature-jump measurements of oligonucleotide dehybridization. Model predictions are directly related to experiments through computed melting curves. While the model provides a generally applicable tool, we illustrate specifically how it is used to interpret equilibrium and nonequilibrium infrared spectroscopy measurements and validate that the model correctly captures sequence and length dependent effects for sequences up to 18 nucleotides. Introducing a single free parameter for the excess entropy per unpaired nucleotide results in reasonable agreement with experiment. Translational entropy and concentration effects are modeled through a coarser lattice of single-strand sized sites. The conformational degrees of freedom of unpaired nucleotides in the single-strand or duplex state are modeled as self-avoiding walks of the polymer chain on a cubic lattice. Our model is a statistical extension of the nearest-neighbor model in which all possible combinations of broken and intact base pairs in the duplex state are considered explicitly. We present a lattice model developed to interpret oligonucleotide hybridization experiments beyond the two-state, all-or-none description.
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