Uncovering multiloci-ordering by algebraic property of Laplacian matrix and its Fiedler vector

Motivation: The loci-ordering, based on two-point recombination fractions for a pair of loci, is the most important step in constructing a reliable and fine genetic map. Results: Using the concept from complex graph theory, here we propose a Laplacian ordering approach which uncovers the loci-ordering of multiloci simultaneously. The algebraic property for a Fiedler vector of a Laplacian matrix, constructed from the recombination fraction of the loci-ordering for 26 loci of barley chromosome IV, 846 loci of Arabidopsis thaliana and 1903 loci of Malus domestica, together with the variable threshold uncovers their loci-orders. It offers an alternative yet robust approach for ordering multiloci. Availability and implementation: Source code program with data set is available as supplementary data and also in a software category of the website (http://biophysics.dgist.ac.kr) Contact: or [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online. © 2015 The Author 2015. Published by Oxford University Press. All rights reserved.

Effects of Macromolecular Crowding on Amyloid Beta (16-22) Aggregation Using Coarse-Grained Simulations

To examine the effect of crowding on protein aggregation, discontinuous molecular dynamics (DMD) simulations combined with an intermediate resolution protein model, PRIME20, were applied to a peptide/crowder system. The systems contained 192 Aβ(16-22) peptides and crowders of diameters 5, 20, and 40 Å, represented here by simple hard spheres, at crowder volume fractions of 0.00, 0.10, and 0.20. Results show that both crowder volume fraction and crowder diameter have a large impact on fibril and oligomer formation. The addition of crowders to a system of peptides increases the rate of oligomer formation, shifting from a slow ordered formation of oligomers in the absence of crowders, similar to nucleated polymerization, to a fast collapse of peptides and subsequent rearrangement characteristic of nucleated conformational conversion with a high maximum in the number of peptides in oligomers as the total crowder surface area increases. The rate of conversion from oligomers to fibrils also increases with increasing total crowder surface area, giving rise to an increased rate of fibril growth. In all cases, larger volume fractions and smaller crowders provide the greatest aggregation enhancement effects. We also show that the size of the crowders influences the formation of specific oligomer sizes. In our simulations, the 40 Å crowders enhance the number of dimers relative to the numbers of trimers, hexamers, pentamers, and hexamers, while the 5 Å crowders enhance the number of hexamers relative to the numbers of dimers, trimers, tetramers, and pentamers. These results are in qualitative agreement with previous experimental and theoretical work. © 2014 American Chemical Society.

Impact of sequence on the molecular assembly of short amyloid peptides

The goal of this work is to understand how the sequence of a protein affects the likelihood that it will form an amyloid fibril and the kinetics along the fibrillization pathway. The focus is on very short fragments of amyloid proteins since these play a role in the fibrillization of the parent protein and can form fibrils themselves. Discontinuous molecular dynamics simulations using the PRIME20 force field were performed of the aggregation of 48-peptide systems containing SNQNNF (PrP (170-175)), SSTSAA (RNaseA(15-20)), MVGGVV (Aβ(35-40)), GGVVIA (Aβ(37-42)), and MVGGVVIA (Aβ(35-42)). In our simulations SNQQNF, SSTTSAA, and MVGGVV form large numbers of fibrillar structures spontaneously (as in experiment). GGVVIA forms β-sheets that do not stack into fibrils (unlike experiment). The combination sequence MVGGVVIA forms less fibrils than MVGGVV, hindered by the presence of the hydrophobic residues at the C-terminal. Analysis of the simulation kinetics and energetics reveals why MVGGVV forms fibrils and GGVVIA does not, and why adding I and A to MVGGVVIA reduces fibrillization and enhances amorphous aggregation into oligomeric structures. The latter helps explain why Aβ(1-42) assembles into more complex oligomers than Aβ(1-40), a consequence of which is that it is more strongly associated with Alzheimer's disease. © 2014 Wiley Periodicals, Inc.

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 beta 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