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Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the N-terminal fragment of the Huntingtin (Htt) protein. Structural properties of Htt N-terminal regions and the molecular mechanism leading to protein aggregation have not been fully explained yet. We performed all-atom replica exchange molecular dynamics to investigate the structures of Htt N-terminal parts with polyQ tracts of nonpathogenic and pathogenic lengths. The monomers were composed of the headpiece (17 N-terminal residues), a polyQ tract (polyQ(17) for native and polyQ(55) for pathogenic sequence), and a polyP(11) region, followed by 17 amino acids of mixed sequence. We found that corresponding regions in both fragments fold to similar secondary structures; the headpiece and polyQ stretch adopt mainly α-helical conformations, and polyP(11) forms the PP II-type helix. The native N-terminal fragment is more compact and stabilized by hydrophobic interactions between the surface of polyP(11) and the amphipathic helix of the headpiece. In the pathogenic fragment the headpiece is solvent exposed and does not interact with polyP(11). The predicted structure of the native N-terminal fragment agrees with the X-ray structure of the Htt first exon containing polyQ(17). The structure of the pathogenic fragment adheres to an aggregation model that is mediated by the Htt headpiece.

Molecular dynamics (MD) simulations with implicit solvent and variable protonation states for titratable residues at constant pH are performed for a short peptide derived from ovomucoid third domain (OMTKY3), acetyl-Ser-Asp-Asn-Lys-Thr-Tyr-Gly-amide (residues 26-32 of OMTKY3). Nuclear magnetic resonance (NMR) measurements indicate that the pK(a) for Asp is 3.6. However, if the charge on Lys is neutralized by acetylation, then the pK(a) for Asp is 4.0. These pK(a)'s, and therefore the Asp-Lys interaction, are insensitive to changes in ionic strength. The constant-pH MD simulations for both variants of the heptapeptide yield Asp pK(a) values that are 0.6-0.9 pH units greater than experimental values, but the difference between the variants that is observed in the NMR experiments is reproduced much better. Moreover, the simulations suggest that Asp-Lys interactions do not dominate the behavior of this heptapeptide, even for normal Lys residue where there is a possibility of forming a salt bridge between negatively charged Asp and positively charged Lys. This is consistent with the experimentally observed independence of Asp pK(a) values with respect to ionic strength. Another important result of the simulations with variable protonation states is that they lead to ensembles of the heptapeptide structures that are different from those derived from simulations with fixed protonation states. It should be stressed that these results are for structures generated entirely by computer simulations without any restrictions imposed by experimental data.

An electrostatic field rotates, slides, and guides the kinesin head to bind the microtubule at a site a short distance ahead, thus determining the direction of movement of the motor.

Biochemical reactions in living systems occur in complex, heterogeneous media with total concentrations of macromolecules in the range of 50 - 400 mgml. Molecular species occupy a significant fraction of the immersing medium, up to 40% of volume. Such complex and volume-occupied environments are generally termed 'crowded' and/or 'confined'. In crowded conditions non-specific interactions between macromolecules may hinder diffusion - a major process determining metabolism, transport, and signaling. Also, the crowded media can alter, both qualitatively and quantitatively, the reactions in vivo in comparison with their in vitro counterparts. This review focuses on recent developments in particle-based Brownian dynamics algorithms, their applications to model diffusive transport in crowded systems, and their abilities to reproduce and predict the behavior of macromolecules under in vivo conditions.