In recent years, the field of terahertz (THz) science and technology has entered a completely new phase of unprecedented expansion that is generating ever growing levels of broad-based international attention. In particular,there have been important advances in state-of-the-art THz technology and very enthusiastic growth in research activities associated with related scientific and industrial applications. One can legitimately argue that the potential payoffs of THz sensing and imaging (THz S&I) to application areas such as defense, security, biology and medicine are the major drivers of this new phenomenon. However, there remain major science and technology "gaps" in the THz regime that must be reconciled before many of the perceived payoffs ever become realizable. Therefore, it is natural to ask the question "Is now the time for THz?" or rather, are these recent events just a repeat of previous cycles in THz overenthusiasm that have been witnessed during the last century? The main goal of this paper is to consider some of the most promising THz S&I applications within the specific context of their particular science and technology challenges in an attempt to credibly judge (or speculate on) their future potential.

Terahertz Frequency Sensing and Imaging: A Time of Reckoning Future Applications?

Computational studies of large macromolecular assemblages have come a long way during the past 10 years. With the explosion of computer power and parallel computing, timescales of molecular dynamics simulations have been extended far beyond the hundreds of picoseconds timescale. However, limitations remain for studies of large-scale conformational changes occurring on timescales beyond nanoseconds, especially for large macromolecules. In this review, we describe recent methods based on normal mode analysis that have enabled us to study dynamics on the microsecond timescale for large macromolecules using different levels of coarse graining, from atomically detailed models to those employing only low-resolution structural information. Emerging from such studies is a control principle for robustness in Nature's machines. We discuss this idea in the context of large-scale functional reorganization of the ribosome, virus particles, and the muscle protein myosin.

SYMMETRY, FORM, AND SHAPE: Guiding Principles for Robustness in Macromolecular Machines

DNA bending by small, mobile multivalent cations.

The terahertz frequency absorption spectraof DNA molecules reflect low-frequencyinternal helical vibrations involvingrigidly bound subgroups that are connectedby the weakest bonds, including thehydrogen bonds of the DNA base pairs,and/or non-bonded interactions. Althoughnumerous difficulties make the directidentification of terahertz phonon modes inbiological materials very challenging, ourresearch has shown that such measurementsare both possible and fruitful. Spectra ofdifferent DNA samples reveal a large numberof modes and a reasonable level ofsequence-specific uniqueness. In an attemptto show that the long wavelength absorptionfeatures are intrinsic properties ofbiological materials determined by phononmodes, a normal mode analysis has been usedto predict the absorption spectra ofpolynucleotide RNA Poly[G]-Poly[C]. Directcomparison demonstrated a correlationbetween calculated and experimentallyobserved spectra of the RNA polymers, thusconfirming that the fundamental physicalnature of the observed resonance structureis caused by the internal vibration modesin the macromolecules.In this work we demonstrate results fromFourier-Transform Infrared (FTIR)spectroscopy of DNA macromolecules andrelated biological materials in theterahertz frequency range. Carefulattention was paid to the possibility ofinterference or etalon effects in thesamples, and phenomena were clearlydifferentiated from the actual phononmodes. In addition, we studied thedependence of transmission spectra ofaligned DNA and polynucleotide film sampleson molecule orientation relative to theelectromagnetic field, showing the expectedchange in mode strength as a function ofsample orientation. Further, the absorptioncharacteristics were extracted from thetransmission data using the interferencespectroscopy technique, and a stronganisotropy of terahertz characteristics wasdemonstrated.

THz-Spectroscopy of Biological Molecules.

Based on phase-matched collinear difference-frequency generation in a single GaSe crystal, continuously tunable and coherent radiation in the extremely wide ranges of 2.7–38.4 and 58.2–3540 μm has been achieved. This unique source has the additional advantages of high coherence (narrow linewidth) and simple alignment. The peak output power for the terahertz radiation reaches 209 W at the wavelength of 196 μm (1.53 THz), which corresponds to a power conversion efficiency of 0.055%. Moreover, the terahertz transmission spectra on DNA macromolecules and protein were directly measured, demonstrating some potential and important applications of this terahertz source.

A monochromatic and high-power terahertz source tunable in the ranges of 2.7–38.4 and 58.2–3540 μm for variety of potential applications

We present a computational method which couples normal mode analysis in internal coordinates of a molecule with very far IR spectroscopy. The analytical expression for the dependence of IR absorption on frequency incorporates frequencies and optical activities of each normal mode. In order to predict far-IR spectra of a molecule we evaluate the optical activity of each normal mode. This optical activity is determined by the vibration amplitude of the dipole moment produced by a normal mode. We calculated normal modes of DNA double-helical fragments (dA)12 · (dT)12 and (dA-dT)6 · (dA-dT)6 and evaluated their optical activities. These were found to be very sensitive to the DNA base-pair sequence. The positions of the resonance peaks in the calculated absorption spectrum of (dA)12 · (dT)12 are in a good agreement with those obtained by Fourier transform IR spectroscopy (Powell JW et al. 1987 Phys Rev A 35: 3929–3939).

Prediction of DNA far-IR absorption spectra based on normal mode analysis

Normal mode calculations for two alternating sequence dodecamers in A, B, and Z conformations have been performed in dihedral angle space extended to endocyclic valence angles to account for sugar ring flexibility. Normal modes are analyzed in terms of helicoidal and backbone parameter variations with special attention being paid to global deformations of the double helix such as bending, twisting, or stretching. Results show that the allomorphic form of DNA has the largest influence on the flexibility of the sugar-phosphate backbone. Amplitudes of these vibrations follow the order: B > Z > A. In contrast, the amplitudes of helicoidal parameter variations are much more dependent on the base sequence. Global deformations of the double helix occur with characteristic times in the range of 1 to 10 ps and can be of mixed character, the strongest bending mode being at the same the time strongest stretching mode. © 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 796–811, 1997

Calculation and analysis of low frequency normal modes for DNA

DNA-drug complexes are important because of their pharmacological interest but, in addition, they provide a useful model to study the essential aspects of DNA recognition processes. In order to investigate the influence of ligand binding on the dynamic properties of DNA we have carried out normal mode analysis for complexes with drugs of two types: a typical intercalator, 9-aminoacridine, and a typical groove binder, netropsin. Normal modes are analysed in terms of helicoidal parameter variations with special attention being paid to global deformations of the double helix. The results show that the influence of these two drugs is very different. Intercalation of 9-aminoacridine leads to an increase in the flexibility of the intercalated dinucleotide step, with notably larger vibrational amplitudes for both roll and twist parameters compared to free DNA. In contrast, the groove binding of netropsin induces a stiffening of the DNA segment which is in contact with the drug reflected by decreased vibrational amplitudes for backbone angles and inter base pair helicoidal parameters and an increase in vibrations for adjacent base pairs in terms of buckle and propeller twist.

Influence of drug binding on DNA flexibility: a normal mode analysis.

Sequence specificity of bacteriophage 434 repressor-operator complexation

A theoretical study is presented of the influence of salt bridges between cationic side chains and DNA phosphates on DNA conformation and flexibility. The DNA sequence studied is that of the catabolite activator protein binding oligomer from the crystallized complex. The effect of salt bridges is modeled by neutralization of net phosphate charges for the groups involved in such interactions in the crystallized complex. Energy-optimized conformations are obtained by molecular mechanics using the JUMNA program. Base sequence dependence is studied by moving the phosphate neutralization pattern along the sequence and also by point mutations. Normal mode analysis is used to evaluate DNA flexibility. The results obtained show that the free oligomer is already precurved in the direction favored by the protein, and the effect of phosphate neutralization is principally to increase this curvature. This effect is, however, strongly sequence dependent. In addition, it is shown that oligomer flexibility cannot be explained by a simple superposition of the properties of successive dinucleotide steps, strong long-range coupling effects are observed. In all the cases examined, phosphate neutralization, however, leads to a reduction in oligomer flexibility.A theoretical study is presented of the influence of salt bridges between cationic side chains and DNA phosphates on DNA conformation and flexibility. The DNA sequence studied is that of the catabolite activator protein binding oligomer from the crystallized complex. The effect of salt bridges is modeled by neutralization of net phosphate charges for the groups involved in such interactions in the crystallized complex. Energy-optimized conformations are obtained by molecular mechanics using the JUMNA program. Base sequence dependence is studied by moving the phosphate neutralization pattern along the sequence and also by point mutations. Normal mode analysis is used to evaluate DNA flexibility. The results obtained show that the free oligomer is already precurved in the direction favored by the protein, and the effect of phosphate neutralization is principally to increase this curvature. This effect is, however, strongly sequence dependent. In addition, it is shown that oligomer flexibility cannot be explained by a simple superposition of the properties of successive dinucleotide steps, strong long-range coupling effects are observed. In all the cases examined, phosphate neutralization, however, leads to a reduction in oligomer flexibility.

Tap Ha Duong

Papers

Prediction of DNA far-IR absorption spectra based on normal mode analysis

Calculation and analysis of low frequency normal modes for DNA

Influence of drug binding on DNA flexibility: a normal mode analysis.

Sequence specificity of bacteriophage 434 repressor-operator complexation

The role of DNA-protein salt bridges in molecular recognition: a model study.