Atomistic molecular dynamics simulations of tubulin heterodimers explain the motion of a microtubule.

Microtubules are essential parts of the cytoskeleton that are built by polymerization of tubulin heterodimers into a hollow tube. Regardless that their structures and functions have been comprehensively investigated in a modern soft matter, it is unclear how properties of tubulin heterodimer influence and promote the self-assembly. A detailed knowledge of such structural mechanisms would be helpful in drug design against neurodegenerative diseases, cancer, diabetes etc. In this work atomistic molecular dynamics simulations were used to investigate the fundamental dynamics of tubulin heterodimers in a sheet and a short microtubule utilizing well-equilibrated structures. The breathing motions of the tubulin heterodimers during assembly show that the movement at the lateral interface between heterodimers (wobbling) dominates in the lattice. The simulations of the protofilament curvature agrees well with recently published experimental data, showing curved protofilaments at polymerization of the microtubule plus end. The tubulin heterodimers exposed at the microtubule minus end were less curved and displayed altered interactions at the site of sheet closure around the outmost heterodimers, which may slow heterodimer binding and polymerization, providing a potential explanation for the limited dynamics observed at the minus end.

Molecular Insights into Dipole Relaxation Processes in Water-Lysine Mixtures.

Dielectric spectroscopy is a robust method to investigate relaxations of molecular dipoles. It is particularly useful for studies of biological solutions because of the potential of this method to cover a broad range of dynamical time scales typical for such systems. However, this technique does not provide any information about the nature of the molecular motions, which leads to a certain underemployment of dielectric spectroscopy for gaining microscopic understanding of material properties. For such detailed understanding, computer simulations are valuable tools because they can provide information about the nature of molecular motions observed by, for example, dielectric spectroscopy and to further complement them with structural information. In this work, we acquire information about the nature of dipole relaxation, in n-lysine solutions by means of molecular dynamics simulations. Our results indicate that the experimentally observed main relaxation process of n-lysine has different origins for the single monomer and the polypeptide chains. The relaxation of 1-lysine is due to the motions of whole molecules, whereas the experimentally observed relaxation of 3-lysine and 4-lysine is due to the motions of the residues, which, in turn, are promoted by water relaxation. Furthermore, we propose a new structural model of the lysine amino acids, which can quantitatively account for the experimental dielectric relaxation data. Hydrogen bonding and the structure of water are also discussed in terms of their influence on relaxation processes.

Transient isomers in the photodissociation of bromoiodomethane.

The photochemistry of halomethanes is fascinating for the complex cascade reactions toward either the parent or newly synthesized molecules. Here, we address the structural rearrangement of photodissociated CH2IBr in methanol and cyclohexane, probed by time-resolved X-ray scattering in liquid solution. Upon selective laser cleavage of the C-I bond, we follow the reaction cascade of the two geminate geometrical isomers, CH2I-Br and CH2Br-I. Both meta-stable isomers decay on different time scales, mediated by solvent interaction, toward the original parent molecule. We observe the internal rearrangement of CH2Br-I to CH2I-Br in cyclohexane by extending the time window up to 3 µs. We track the photoproduct kinetics of CH2Br-I in methanol solution where only one isomer is observed. The effect of the polarity of solvent on the geminate recombination pathways is discussed.

Solution x-ray scattering and structure formation in protein dynamics.

We propose a computationally effective approach that builds on Landau mean-field theory in combination with modern nonequilibrium statistical mechanics to model and interpret protein dynamics and structure formation in small- to wide-angle x-ray scattering (S/WAXS) experiments. We develop the methodology by analyzing experimental data in the case of Engrailed homeodomain protein as an example. We demonstrate how to interpret S/WAXS data qualitatively with a good precision and over an extended temperature range. We explain experimental observations in terms of protein phase structure, and we make predictions for future experiments and for how to analyze data at different ambient temperature values. We conclude that the approach we propose has the potential to become a highly accurate, computationally effective, and predictive tool for analyzing S/WAXS data. For this, we compare our results with those obtained previously in an all-atom molecular dynamics simulation.

Deconvoluting Protein (Un)folding Structural Ensembles Using X-Ray Scattering, Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Simulation.

The folding and unfolding of protein domains is an apparently cooperative process, but transient intermediates have been detected in some cases. Such (un)folding intermediates are challenging to investigate structurally as they are typically not long-lived and their role in the (un)folding reaction has often been questioned. One of the most well studied (un)folding pathways is that of Drosophila melanogaster Engrailed homeodomain (EnHD): this 61-residue protein forms a three helix bundle in the native state and folds via a helical intermediate. Here we used molecular dynamics simulations to derive sample conformations of EnHD in the native, intermediate, and unfolded states and selected the relevant structural clusters by comparing to small/wide angle X-ray scattering data at four different temperatures. The results are corroborated using residual dipolar couplings determined by NMR spectroscopy. Our results agree well with the previously proposed (un)folding pathway. However, they also suggest that the fully unfolded state is present at a low fraction throughout the investigated temperature interval, and that the (un)folding intermediate is highly populated at the thermal midpoint in line with the view that this intermediate can be regarded to be the denatured state under physiological conditions. Further, the combination of ensemble structural techniques with MD allows for determination of structures and populations of multiple interconverting structures in solution.

Determination of nanostructure of liposomes containing two model drugs by X-ray scattering from a synchrotron source.

Small-angle X-ray scattering has been employed to study how the introduction of paracetamol and acetylsalicylic acid into a liposome bilayer system affects the system's nanostructure. An X-ray scattering model, developed for multilamellar liposome systems [Pabst et al. (2000), Phys. Rev. E, 62, 4000-4009], has been used to fit the experimental data and to extract information on how structural parameters, such as the number and thickness of the bilayers of the liposomes, thickness of the water layer in between the bilayers, size and volume of the head and tail groups, are affected by the drugs and their concentration. Even though the experimental data reveal a complicated picture of the drug-bilayer interaction, they clearly show a correlation between nanostructure, drug and concentration in some aspects. The localization of the drugs in the bilayers is discussed.