Iksoo Chang

Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils

Increasing evidence indicates that oligomeric protein assemblies may represent the molecular species responsible for cytotoxicity in a range of neurological disorders including Alzheimer and Parkinson diseases. We use all-atom computer simulations to reveal that the process of oligomerization can be divided into two steps. The first is characterised by a hydrophobic coalescence resulting in the formation of molten oligomers in which hydrophobic residues are sequestered away from the solvent. In the second step, the oligomers undergo a process of reorganisation driven by interchain hydrogen bonding interactions that induce the formation of β sheet rich assemblies in which hydrophobic groups can become exposed. Our results show that the process of aggregation into either ordered or amorphous species is largely determined by a competition between the hydrophobicity of the amino acid sequence and the tendency of polypeptide chains to form arrays of hydrogen bonds. We discuss how the increase in solvent-exposed hydrophobic surface resulting from such a competition offers an explanation for recent observations concerning the cytotoxicity of oligomeric species formed prior to mature amyloid fibrils.

Extending the PRIME model for protein aggregation to all 20 amino acids

We extend PRIME, an intermediate‐resolution protein model previously used in simulations of the aggregation of polyalanine and polyglutamine, to the description of the geometry and energetics of peptides containing all 20 amino acid residues. The 20 amino acid side chains are classified into 14 groups according to their hydrophobicity, polarity, size, charge, and potential for side chain hydrogen bonding. The parameters for extended PRIME, called PRIME 20, include hydrogen‐bonding energies, side chain interaction range and energy, and excluded volume. The parameters are obtained by applying a perceptron‐learning algorithm and a modified stochastic learning algorithm that optimizes the energy gap between 711 known native states from the PDB and decoy structures generated by gapless threading. The number of independent pair interaction parameters is chosen to be small enough to be physically meaningful yet large enough to give reasonably accurate results in discriminating decoys from native structures. The most physically meaningful results are obtained with 19 energy parameters. Proteins 2010.

Functional Implications of an Intermeshing Cogwheel-Like Interaction between TolC and MacA in the Action of Macrolide-Specific Efflux Pump MacAB-TolC

Macrolide-specific efflux pump MacAB-TolC has been identified in diverse Gram-negative bacteria including Escherichia coli. The inner membrane transporter MacB requires the outer membrane factor TolC and the periplasmic adaptor protein MacA to form a functional tripartite complex. In this study, we used a chimeric protein containing the tip region of the TolC α-barrel to investigate the role of the TolC α-barrel tip region with regard to its interaction with MacA. The chimeric protein formed a stable complex with MacA, and the complex formation was abolished by substitution at the functionally essential residues located at the MacA α-helical tip region. Electron microscopic study delineated that this complex was made by tip-to-tip interaction between the tip regions of the α-barrels of TolC and MacA, which correlated well with the TolC and MacA complex calculated by molecular dynamics. Taken together, our results demonstrate that the MacA hexamer interacts with TolC in a tip-to-tip manner, and implies the manner by which MacA induces opening of the TolC channel.

Pre-structured motifs in the natively unstructured preS1 surface antigen of hepatitis B virus

The preS1 surface antigen of hepatitis B virus (HBV) is known to play an important role in the initial attachment of HBV to hepatocytes. We have characterized structural features of the full‐length preS1 using heteronuclear NMR methods and discovered that this 119‐residue protein is inherently unstructured without a unique tertiary structure under a nondenaturing condition. Yet, combination of various NMR parameters shows that the preS1 contains “pre‐structured” domains broadly covering its functional domains. The most prominent domain is formed by residues 27–45 and overlaps with the putative hepatocyte‐binding domain (HBD) encompassing residues 21–47, within which two well‐defined pre‐structured motifs, formed by Pro32–Ala36 and Pro41–Phe45 are found. Additional, somewhat less prominent, pre‐structured motifs are also formed by residues 11–18, 22–25, 37–40, and 46–50. Overall results suggest that the preS1 is a natively unstructured protein (NUP) whose N‐terminal 50 residues, populated with multiple pre‐structured motifs, contribute critically to hepatocyte binding.

Spontaneous Formation of Twisted Aβ16-22 Fibrils in Large-Scale Molecular-Dynamics Simulations

Protein aggregation is associated with fatal neurodegenerative diseases, including Alzheimers and Parkinsons. Mapping out kinetics along the aggregation pathway could provide valuable insights into the mechanisms that drive oligomerization and fibrillization, but that is beyond the current scope of computational research. Here we trace out the full kinetics of the spontaneous formation of fibrils by 48 Aβ(16-22) peptides, following the trajectories in molecular detail from an initial random configuration to a final configuration of twisted protofilaments with cross-β-structure. We accomplish this by performing large-scale molecular-dynamics simulations based on an implicit-solvent, intermediate-resolution protein model, PRIME20. Structural details such as the intersheet distance, perfectly antiparallel β-strands, and interdigitating side chains analogous to a steric zipper interface are explained by and in agreement with experiment. Two characteristic fibrillization mechanisms - nucleation/templated growth and oligomeric merging/structural rearrangement - emerge depending on the temperature.

COMPUTER SIMULATION STUDY OF AMYLOID FIBRIL FORMATION BY PALINDROMIC SEQUENCES IN PRION PEPTIDES

We simulate the aggregation of large systems containing palindromic peptides from the Syrian hamster prion protein SHaPrP 113–120 (AGAAAAGA) and the mouse prion protein MoPrP 111–120 (VAGAAAAGAV) and eight sequence variations: GAAAAAAG, (AG)4, A8, GAAAGAAA, A10, V10, GAVAAAAVAG, and VAVAAAAVAV The first two peptides are thought to act as the Velcro that holds the parent prion proteins together in amyloid structures and can form fibrils themselves. Kinetic events along the fibrillization pathway influence the types of structures that occur and variations in the sequence affect aggregation kinetics and fibrillar structure. Discontinuous molecular dynamics simulations using the PRIME20 force field are performed on systems containing 48 peptides starting from a random coil configuration. Depending on the sequence, fibrillar structures form spontaneously over a range of temperatures, below which amorphous aggregates form and above which no aggregation occurs. AGAAAAGA forms well organized fibrillar structures whereas VAGAAAAGAV forms less well organized structures that are partially fibrillar and partially amorphous. The degree of order in the fibrillar structure stems in part from the types of kinetic events leading up to its formation, with AGAAAAGA forming less amorphous structures early in the simulation than VAGAAAAGAV. The ability to form fibrils increases as the chain length and the length of the stretch of hydrophobic residues increase. However as the hydrophobicity of the sequence increases, the ability to form well‐ordered structures decreases. Thus, longer hydrophobic sequences form slightly disordered aggregates that are partially fibrillar and partially amorphous. Subtle changes in sequence result in slightly different fibril structures. Proteins 2011;

Fundamental judgement in Cont–Bouchaud Herding model of market fluctuations

The percolation model of Cont and Bouchaud for the herding of noise traders is generalized to take into account also the fundamental value of the traded object, not only the behaviour of other traders. Monte Carlo simulations with 10012 and 77 traders give no drastic change in the histogram of price jumps and in the decay of the volatility. The price itself, however, stays close to its fundamental value instead of diffusing away from it.

Cooperative folding kinetics of BBL protein and peripheral subunit-binding domain homologues

Recent experiments claiming that Naf-BBL protein follows a global downhill folding raised an important controversy as to the folding mechanism of fast-folding proteins. Under the global downhill folding scenario, not only do proteins undergo a gradual folding, but folding events along the continuous folding pathway also could be mapped out from the equilibrium denaturation experiment. Based on the exact calculation using a free energy landscape, relaxation eigenmodes from a master equation, and Monte Carlo simulation of an extended Muñoz–Eaton model that incorporates multiscale-heterogeneous pairwise interactions between amino acids, here we show that the very nature of a two-state cooperative transition such as a bimodal distribution from an exact free energy landscape and biphasic relaxation kinetics manifest in the thermodynamics and folding–unfolding kinetics of BBL and peripheral subunit-binding domain homologues. Our results provide an unequivocal resolution to the fundamental controversy related to the global downhill folding scheme, whose applicability to other proteins should be critically reexamined.

Influence of temperature on formation of perfect tau fragment fibrils using PRIME20/DMD simulations.

We investigate the fibrillization process for amyloid tau fragment peptides (VQIVYK) by applying the discontinuous molecular dynamics method to a system of 48 VQIVYK peptides modeled using a new protein model/force field, PRIME20. The aim of the article is to ascertain which factors are most important in determining whether or not a peptide system forms perfect coherent fibrillar structures. Two different directional criteria are used to determine when a hydrogen bond occurs: the original H‐bond constraints and a parallel preference H‐bond constraint that imparts a slight bias towards the formation of parallel versus antiparallel strands in a β‐sheet. Under the original H‐bond constraints, the resulting fibrillar structures contain a mixture of parallel and antiparallel pairs of strands within each β‐sheet over the whole fibrillization temperature range. Under the parallel preference H‐bond constraints, the β‐sheets within the fibrillar structures are more likely to be parallel and indeed become perfectly parallel, consistent with X‐ray crystallography, at a high temperature slightly below the fibrillization temperature. The high temperature environment encourages the formation of perfect fibril structures by providing enough time and space for peptides to rearrange during the aggregation process. There are two different kinetic mechanisms, template assembly with monomer addition at high temperature and merging/rearrangement without monomer addition at low temperature, which lead to significant differences in the final fibrillar structure. This suggests that the diverse fibril morphologies generally observed in vitro depend more on environmental conditions than has heretofore been appreciated.

Series expansion study of quantum percolation on the square lattice

Abstract:We study the site and bond quantum percolation model on the two-dimensional square lattice using series expansion in the low concentration limit. We calculate series for the averages of , where Tij(E) is the transmission coefficient between sites i and j, for k=0, 1, , 5 and for several values of the energy E near the center of the band. In the bond case the series are of order p14 in the concentration p(some of those have been formerly available to order p10) and in the site case of order p16. The analysis, using the Dlog-Padé approximation and the techniques known as M1 and M2, shows clear evidence for a delocalization transition (from exponentially localized to extended or power-law-decaying states) at an energy-dependent threshold pq(E) in the range , confirming previous results (e.g. and for bond and site percolation) but in contrast with the Anderson model. The divergence of the series for different kis characterized by a constant gap exponent, which is identified as the localization length exponent from a general scaling assumption. We obtain estimates of . These values violate the bound of Chayes et al.