Jonggu Jeon

Computational Vibrational Spectroscopy of Peptides and Proteins in One and Two Dimensions

Vibrational spectroscopy provides direct information on molecular environment and motions but, its interpretation is often hampered by band broadening. Over the past decade, two-dimensional (2D) vibrational spectroscopy has emerged as a promising technique to overcome a number of difficulties associated with linear spectroscopy and provided significantly detailed information on the structure and dynamics of complex molecules in condensed phases. This Account reviews recently developed computational methods used to simulate 1D and 2D vibrational spectra. The central quantity to calculate in computational spectroscopy is the spectroscopic response function, which is the product of many contributing factors such as vibrational transition energies, transition moments, and their modulations by fluctuating local environment around a solute. Accurate calculations of such linear and nonlinear responses thus require a concerted effort employing a wide range of methods including electronic structure calculation (ESC) and molecular dynamics (MD) simulation. The electronic structure calculation can provide fundamental quantities such as normal-mode frequencies and transition multipole strengths. However, since the treatable system size is limited with this method, classical MD simulation has also been used to account for the dynamics of the solvent environment. To achieve chemical accuracy, these two results are combined to generate time series of fluctuating transition frequencies and transition moments with the distributed multipole analysis, and this particular approach has been known as the hybrid ESC/MD method. For coupled multichromophore systems, vibrational properties of each chromophore such as a peptide are individually calculated by electronic structure methods and the Hessian matrix reconstruction scheme was used to obtain local mode frequencies and couplings of constituting anharmonic oscillators. The spectra thus obtained, especially for biomolecules including polypeptides and proteins, have proven to be reliable and in good agreement with experimental spectra. An alternative to the hybrid method has also been developed, where the classical limit of the vibrational response function was considered. Its main attraction is the capability to obtain the spectra directly from a set of MD trajectories. A novel development along this direction has been achieved by using quantum mechanical/molecular mechanical (QM/MM) force fields for the accurate description of vibrational anharmonicity and chromophore polarization effects. The latter aspects are critical in the 2D case because classical force fields employing harmonic intramolecular potential cannot produce reliable 2D signal. We anticipate that the computational methods presented here will continue to evolve along with experimental advancements and will be of use to further elucidate ultrafast dynamics of chemical and biological systems.

Direct quantum mechanical/molecular mechanical simulations of two-dimensional vibrational responses: N-methylacetamide in water

Multidimensional infrared (IR) spectroscopy has emerged as a viable tool to study molecular structure and dynamics in condensed phases, and the third-order vibrational response function is the central quantity underlying various nonlinear IR spectroscopic techniques, such as pump–probe, photon echo and two-dimensional (2D) IR spectroscopy. In this paper, a new computational method is presented that calculates this nonlinear response function in the classical limit from a series of classical molecular dynamics (MD) simulations, employing a quantum mechanical/molecular mechanical (QM/MM) force field. The method relies on the stability matrix formalism where the dipole–dipole quantum mechanical commutators appearing in the exact quantum response function are replaced by the corresponding Poisson brackets. We present the formulation and computational algorithm of the method for both the classical and the QM/MM force fields and apply it to the 2D IR spectroscopy of carbon monoxide (CO) and N-methylacetamide (NMA), each solvated in a water cluster. The conventional classical force field with harmonic bond potentials is shown to be incapable of producing a reliable 2D IR signal because intramolecular vibrational anharmonicity, essential to the production of the nonlinear signal, is absent in such a model. The QM/MM force field, on the other hand, produces distinct 2D spectra for the NMA and CO systems with clear vertical splitting and cross peaks, reflecting the vibrational anharmonicities and the vibrational couplings between the underlying vibrational modes, respectively. In the NMA spectrum, the coupling between the amide I and II modes is also well reproduced. While attaining the converged spectrum is found to be challenging with this method, with an adequate amount of computing it can be straightforwardly applied to new systems containing multiple chromophores with little modeling effort, and therefore it would be useful in understanding the multimode 2D IR spectrum of complex molecular systems.

Infrared Probing of 4-Azidoproline Conformations Modulated by Azido Configurations

4-Azidoproline (Azp) can tune the stability of the polyproline II (P(II)) conformation in collagen. The azido group in the 4R and 4S configurations stabilizes and destabilizes the P(II) conformation, respectively. To obtain insights into the dependence of the conformational stability on the azido configuration, we carried out Fourier transform (FT) IR experiments with four 4-azidoproline derivatives, Ac-(4R/S)-Azp-(NH/O)Me. We found that the amide I and azido IR spectra are different depending on the azido configuration and C-terminal structure. The origin of such spectral differences between 4R and 4S configurations and between C-terminal methylamide and ester ends was elucidated by quantum chemistry calculations in combination with (1)H NMR and time- and frequency-resolved IR pump-probe spectroscopy. We found that the azido configurations and C-terminal structures affect intramolecular interactions, which are responsible for the ensuing conformational and thereby IR spectral differences. Consequently, 4-azidoproline conformations modulated by azido configurations can be probed by IR spectroscopy. These findings suggest that 4-azidoproline can be both a structure-control and -probing element, which enables the infrared tracking of proline roles in protein structure, function, and dynamics.

Redistribution of carbonyl stretch mode energy in isolated and solvated N-methylacetamide: Kinetic energy spectral density analyses

The vibrational energy transfer from the excited carbonyl stretch mode in N-deuterated N-methylacetamide (NMA-d), both in isolation and in a heavy water cluster, is studied with nonequilibrium molecular dynamics (NEMD) simulations, employing a quantum mechanical/molecular mechanical (QM∕MM) force field at the semiempirical PM3 level. The nonequilibrium ensemble of vibrationally excited NMA-d is prepared by perturbing the positions and velocities of the carbonyl C and O atoms and its NEMD trajectories are obtained with a leap-frog algorithm properly modified for the initial perturbation. In addition to the time-domain analysis of the kinetic and potential energies, a novel method for the spectral analysis of the atomic kinetic energies is developed, in terms of the spectral density of kinetic energy, which provides the time-dependent changes of the frequency-resolved kinetic energies without the complications of normal mode analysis at every MD time step. Due to the QM description of the solute electronic structure, the couplings among the normal modes are captured more realistically than with classical force fields. The energy transfer in the isolated NMA-d is found to proceed first from the carbonyl bond to other modes with time scales of 3 ps or less, and then among the other modes over 3-21 ps. In the solvated NMA-d, most of the excess energy is first transferred to other intramolecular modes within 5 ps, which is subsequently dissipated to solvent with 7-19 ps time scales. The contribution of the direct energy transfer from the carbonyl bond to solvent was only 5% with ~7 ps time scale. Solvent reorganization that leads to destabilization of the electrostatic interactions is found to be crucial in the long time relaxation of the excess energy, while the water intramolecular modes do not contribute significantly. Detailed mode-specific energy transfer pathways are deduced for the isolated and solvated NMA-d and they show that the energy transfer in NMA-d is a highly cooperative process among the intramolecular modes and there is no single dominant pathway with more than 30% of transient contribution.

An Accurate Classical Simulation of a Two-Dimensional Vibrational Spectrum: OD Stretch Spectrum of a Hydrated HOD Molecule

An accurate computational method for the classical simulation of the two-dimensional vibrational spectra is presented. The method refines our previous computational method for the third order vibrational response function in the classical limit, and it enables capturing the diagonal elongation and its waiting time (T) dependence widely observed in experimental two-dimensional infrared (2D IR) spectra of intramolecular modes. The improvement is achieved by a series of new developments including (i) a block algorithm for the stability matrix computation, (ii) new equations of motion for the position-perturbed molecular dynamics (MD) trajectory, and (iii) enhanced sampling efficiency by exploiting the time-reversal invariance of MD trajectories. The method is applied to the simulation of 2D IR spectra of the OD stretch mode in a hydrated HOD molecule, employing a hybrid quantum mechanical/molecular mechanical force field. The simulated spectra exhibit diagonal elongation of the 2D IR signal at small T, reflecting the correlation of individual transitions among the inhomogeneously broadened ensemble. The slopes of the nodal lines of the elongated signals are found to decay with a time scale of 1.6 ps as T increases, in reasonable agreement with the frequency correlation decay time of 1.2 ps. The amplitudes of the positive and negative peaks also decay as T increases, due to vibrational population relaxation and molecular rotation. The peak positions tend to blue shift with increasing T, reflecting the different relaxation rates of the strongly and weakly solvated HOD species. These results indicate that the present method can reliably predict the waiting-time-dependent changes of 2D IR spectra of a single vibrational chromophore in solution.

Induced Optical Activity of DNA-Templated Cyanine Dye Aggregates: Exciton Coupling Theory and TD-DFT Studies

Certain cyanine dye molecules have been observed to self-assemble in DNA templates to form large chiral aggregates, which exhibit induced circular dichroism. The structure and circular dichroism (CD) of one such system, aggregates of a cationic DiSC2(5) cyanine dye, are investigated using the time-dependent Kohn-Sham density functional theory (TD-DFT) and exciton coupling model. A series of TD-DFT calculations on the aggregates with one, two, and four dye molecules clearly shows the onset of CD induced by the helically twisted structure compatible with the minor groove of DNA templates. More simplified exciton coupling model analysis successfully reproduces the major positive Cotton effect observed in the experiment as well as the TD-DFT calculations, but it is unable to capture minor features of the CD spectrum that are closely related to absolute configurations of constituent dyes in the complex. We assess the performance of various methods used for evaluation of the electronic coupling energies between interacting chromophores. Our results confirm that the interchromophore interactions in cyanine dye aggregates are primarily electrostatic in nature and indicate that the exciton coupling model is adequate for studying induced CD of self-assembled aggregates of cyanine dye molecules.

Simultaneous spectral and temporal analyses of kinetic energies in nonequilibrium systems: theory and application to vibrational relaxation of O-D stretch mode of HOD in water.

A time series of kinetic energies (KE) from classical molecular dynamics (MD) simulation contains fundamental information on system dynamics. It can also be analyzed in the frequency domain through Fourier transformation (FT) of velocity correlation functions, providing energy content of different spectral regions. By limiting the FT time span, we have previously shown that spectral resolution of KE evolution is possible in the nonequilibrium situations [Jeon and Cho, J. Chem. Phys. 2011, 135, 214504]. In this paper, we refine the method by employing the concept of instantaneous power spectra, extending it to reflect an instantaneous time-correlation of velocities with those in the future as well as with those in the past, and present a new method to obtain the instantaneous spectral density of KE (iKESD). This approach enables the simultaneous spectral and temporal resolution of KE with unlimited time precision. We discuss the formal and novel properties of the new iKESD approaches and how to optimize computational methods and determine parameters for practical applications. The method is specifically applied to the nonequilibrium MD simulation of vibrational relaxation of the OD stretch mode in a hydrated HOD molecule by employing a hybrid quantum mechanical/molecular mechanical (QM/MM) potential. We directly compare the computational results with the OD band population relaxation time profiles extracted from the IR pump-probe measurements for 5% HOD in water. The calculated iKESD yields the OD bond relaxation time scale ∼30% larger than the experimental value, and this decay is largely frequency-independent if the classical anharmonicity is accounted for. From the integrated iKESD over intra- and intermolecular bands, the major energy transfer pathways were found to involve the HOD bending mode in the subps range, then the internal modes of the solvent until 5 ps after excitation, and eventually the solvent intermolecular modes. Also, strong hydrogen-bonding of HOD is found to significantly hinder the initial intramolecular energy transfer process.

Ion aggregation in high salt solutions. VII. The effect of cations on the structures of ion aggregates and water hydrogen-bonding network

Ions in high salt solutions have a strong propensity to form polydisperse ion aggregates with broad size and shape distributions. In a series of previous comparative investigations using femtosecond IR pump-probe spectroscopy, molecular dynamics simulation, and graph theoretical analysis, we have shown that there exists a morphological difference in the structures of ion aggregates formed in various salt solutions. As salt concentration increases, the ions in high salt solutions form either cluster-like structures excluding water molecules or network-like structures entwined with water hydrogen-bonding networks. Interestingly, such morphological characteristics of the ion aggregates have been found to be in correlation with the solubility limits of salts. An important question that still remains unexplored is why certain salts with different cations have notably different solubility limits in water. Here, carrying out a series of molecular dynamics simulations of aqueous salt solutions and analyzing the distributions and connectivity patterns of ion aggregates with a spectral graph analysis method, we establish the relationship between the salt solubility and the ion aggregate morphology with a special emphasis on the cationic effects on water structures and ion aggregation. We anticipate that the understanding of large scale ion aggregate structures revealed in this study will be critical for elucidating the specific ion effects on the solubility and conformational stability of co-solute molecules such as proteins in water.

Amide i IR probing of core and shell hydrogen-bond structures in reverse micelles

Abstract The properties of N-methylacetamide (NMA) molecules encapsulated in the reverse micelles (RMs) formed by anionic surfactant aerosol OT (AOT), are studied with vibrational spectroscopy and computation. Vibrational spectra of the amide I′ mode of the fully deuterated NMA-d7 show gradual increase of peak frequencies and line broadening as the size of RMs decreases. Analyses of the spectral features reveal the presence of three states of NMA-d7 that correspond to NMA located in the core of water phase (absorption frequency of 1606 cm–1) and two types of interfacial NMA near the surfactant layer (1620 and 1644 cm–1). In larger RMs with water content w0 = [D2O]/[AOT] ≥ 10, only the first two states are observed, whereas in smaller RMs, the population of the third state grows up to 25 % at w0 = 2. These results indicate the general validity of the two-state core/shell model for the confined aqueous solution of NMA, with small modifications due to the system-dependent solute-interface interaction. However, simulations of small RM systems with w0 ≤ 15 show continuous variations of the population, frequency shifts, and the solute-solvent interaction strengths at solute-interface distance less than 4 Å. Thus, the distinction of solute core/shell states tends to be blurred in small RMs but is still effective in interpreting the average spectroscopic observables.

Human papillomavirus 60-positive epidermal cyst and wart at a nonpalmoplantar location

Wegener granulomatosis, nicorandil, and ergotamine tartrate suppositories. The rapid resolution on stopping nicorandil confirmed this as the cause. Nicorandil can induce both oral and perianal ulceration. Oral ulceration was first reported in 1997. Perianal ulceration is less common since it was reported in 2002 and there have been only 17 cases recorded in the literature. The ulcers are punched out at both locations, with nonspecific histology, but it is not known if they share a common pathogenesis. Patients reported with oral ulceration have not had perianal ulceration, and vice versa. The onset of perianal ulceration after starting nicorandil can vary from several weeks to months, but healing on withdrawal of the drug is characteristic of nicorandil-induced ulceration and has been described in previous cases. In our patient, perianal ulceration was also accompanied by ulceration in areas of flexural psoriasis, which has not been described before. Histology of nicorandil-induced ulcers has not been well described, and in the few cases that have been reported the changes were nonspecific. Elastophagocytosis is a fairly common nonspecific phenomenon in numerous inflammatory dermatoses, but in our case the changes were diffuse and prominent. Drug-induced alteration in elastic tissues is extremely rare and the only other medication that has been documented to cause elastic tissue damage is penicillamine. The histological changes observed in our patient could be an incidental finding or may have been induced by the nicorandil. Report of further cases will help either to confirm or to deny this observation.