From dynamics to structure and function of model biomolecular systems

The purpose of this thesis was to extend recent works on structure and dynamics of hydrogen bonded crystals to model biomolecular systems and biological processes. The tools that we have used are neutron scattering (NS) and density functional theory (DFT) and force field (FF) based simulation methods. The quantitative and parameterfree link (in the case of DFT methods) between structure and dynamics has been applied to strong hydrogen bonded crystals and bio-polymers such as collagen and DNA. In several SSHB crystals, DFT normal modes and molecular dynamics calculations revealed the mechanism of proton transfer as being driven by low frequency phonons. The natural extension of these methods was oriented to polymers. Due to the lack of long range order, obtaining structural information of amorphous bio-polymeric systems requires the determination of the amide bands, which are the vibrations of the peptide groups C(=O)-N-H. We have used the DFT and inelastic neutron scattering approach to determine the spectral profile of the amide-V band and therefore the packing of 2D molecular sheets in Kevlar and the signature of the tertiary structure in Collagen. Depending on the secondary structure, the trends of the amide-I band has been well reproduced for simple polypeptides chains like polyglycine and polyproline. Water surrounding the protein is a huge subject of research. Water molecules are linked together to form different amorphous hydration shells. DFT methods are seen to suffer from a poorly defined minimum in the PES, resulting in negative frequencies in a normal mode analysis. Using force fields methods overcomes this problem but introduces a parameterization of the total energy calculation. In DNA, the structure-dynamics-function that we have focused on is base-pair opening, which is related to various bio-physical processes like replication and transcription. We used force field methods and normal mode analysis to identify modes with base-pair opening character. The oriented DNA films for experiments were made using the wet spinning method and the equipment was successfully installed and modernized during the thesis at ILL.Applied Science

Collagen and component polypeptides: low frequency and amide vibrations.

Collagen is a fibrous protein, which exists widely in the human body. The biomechanical properties of collagen depend on its triple helix structure and the corresponding low frequency vibrations. We use first-principles, density functional theory methods and analytical force fields to investigate the molecular vibrations of a model collagen compound, the results being validated by comparison with published, inelastic neutron scattering data. The results from these atomistic simulations are used at higher frequency to Study the Amide I and V vibrations and therefore the vibrational signature of secondary and tertiary structure formation. In addition to collagen, its component homopolymers, poly-glycine and poly-proline are also studied. The Amide V vibration of glycine is strongly modified in going from the single helix of poly-glycine II to the triple helix of collagen. The collagen models are hydrated and this work allows LIS to discuss the relative merits of density functional theory and force field methods when tackling complex, partially crystalline systems. © 2008, Elsevier Ltd

Atomistic model of DNA: phonons and base-pair opening.

A fully atomistic model of B-DNA using the CHARMM (chemistry at Harvard molecular mechanics) force field is presented. Molecular dynamics simulations were used to prepare an equilibrium structure. The Hessian of interatomic forces obtained from CHARMM for the equilibrium structure was used as input to a large scale phonon calculation. The calculated dispersion relations at low frequency are compared with recently published experimental data, which shows the model to have good accuracy for the low frequency, vibrational modes of DNA. These are discussed in the context of base-pair opening. In addition to the widely reported modes at, or below, ~12.5 meV, a continuous band of modes with strong base-pair opening character is found up to 40 meV, which coincides with the typical denaturation temperature of DNA. © 2007, American Physical Societ

Phonon driven proton transfer in crystals with short strong hydrogen bonds

Recent work on understanding why protons migrate with increasing temperature in short, strong hydrogen bonds is extended here to three more organic, crystalline systems. Inelastic neutron scattering and density functional theory based simulations are used to investigate structure, vibrations, and dynamics of these systems as functions of temperature. The mechanism determined in a previous work on urea phosphoric acid of low frequency vibrations stabilizing average crystal structures, in which the potential energy well of the hydrogen bond has its minimum shifted towards the center of the bond, is found to be valid here. The new feature of the N–HO hydrogen bonds studied in this work is that the proton is transferred from the donor atom to the acceptor atom. Molecular dynamics simulations show that in an intermediate temperature regime, in which the proton is not completely transferred, the proton is bistable, jumping from one side of the hydrogen bond to the other. In the case of 3,5-pyridine dicarboxylic acid, which has been studied in most detail, specific phonons are identified, which influence the potential energy surface of the proton in the short, strong hydrogen bond

Atomistic model of DNA: Phonons and base-pair opening

Applied Science

Force-induced structural transitions in cross-linked DNA films.

We report on the preparation and characterization of wet-spun films of sodium DNA in which intermolecular cross-links were introduced following formaldehyde treatment. Raman scattering shows that the DNA in moderately cross-linked films is mainly in the B conformation. Stretching experiments show a transition from plastic to elastomeric behavior with increasing exposure to the cross-linking agent. Elastomeric DNA films are strongly disordered. X-ray diffraction shows that stretching of moderately cross-linked films under controlled high humidity conditions results in increased molecular orientation as well as the appearance of meridional reflections at 7.4-7.8 and 8.2 angstroms. These reflections are not observed for any of the classical conformations associated with mixed sequence DNA, and may arise from extended base-pair stacking in a stretched DNA structure

How phonons govern the Behavior of short, strong hydrogen bonds in urea-phosphoric acid

Recent neutron diffraction data have shown that the hydrogen atom involved in the short, strong hydrogen bond in urea-phosphoric acid migrates toward the midpoint of the hydrogen bond as the temperature increases. With the help of solid state ab initio calculations and inelastic neutron scattering, we have investigated the temperature dependence of the structural and vibrational properties of the system. The potential energy surface of the proton in the short, strong hydrogen bond and the thermal population of the energy levels therein cannot account for the observed proton migration. Ab initio molecular dynamics simulations clearly reveal the migration of the proton. This molecular dynamics result was reported recently by other authors, but they only offered a tentative explanation in terms of a resonance between high-frequency vibrations, which is not supported by the calculations presented here. We explain the proton migration in terms of phonon-driven structural fluctuations and their impact on the temperature-dependent evolution of the potential energy surface of the short hydrogen-bond proton