Pathogenic mutations in the hydrophobic core of the human prion protein can promote structural instability and misfolding

Transmissible spongiform encephalopathies, or prion diseases, are caused by misfolding and aggregation of the prion protein PrP. These diseases can be hereditary in humans and four of the many disease-associated missense mutants of PrP are in the hydrophobic core: V180I, F198S, V203I and V210I. The T183A mutation is related to the hydrophobic core mutants as it is close to the hydrophobic core and known to cause instability. We have performed extensive molecular dynamics simulations of these five PrP mutants and compared their dynamics and conformations to wild-type PrP. The simulations highlight the changes that occur upon introduction of mutations and help to rationalize experimental findings. Changes can occur around the mutation site, but they can also be propagated over long distances. In particular, the F198S and T183A mutations lead to increased flexibility in parts of the structure that are normally stable, and the short β-sheet moves away from the rest of the protein. Mutations V180I, V210I and, to a lesser extent, V203I cause changes similar to those observed upon lowering the pH, which has been linked to misfolding. Early misfolding is observed in one V180I simulation. Overall, mutations in the hydrophobic core have a significant effect on the dynamics and stability of PrP, including the propensity to misfold, which helps to explain their role in the development of familial prion diseases

Characterization of the unfolding pathway of the cell-cycle protein p13suc1 by molecular dynamics simulations: implications for domain swapping

AbstractBackground: The p13suc1 gene product is a member of the cks (cyclin-dependent protein kinase subunit) protein family and has been implicated in regulation of the cell cycle. Various crystal structures of suc1 are available, including a globular, monomeric form and a β-strand exchanged dimer. It has been suggested that conversions between these forms, and perhaps others, may be important in the regulation of the cell cycle.Results: We have undertaken molecular dynamics simulations of protein unfolding to investigate the conformational properties of suc1. Unfolding transition states were identified for each of four simulations. These states contain some native secondary structure, primarily helix α1 and the core of the β sheet. The hydrophobic core is loosely packed. Further unfolding leads to an intermediate state that is slightly more expanded than the transition state, but with considerably fewer nonlocal, tertiary packing contacts and less secondary structure. The helices are fluctuating but partially formed in the denatured state and β2 and β4 remain associated.Conclusions: It appears that suc1 folds by a nucleation-condensation mechanism, similar to that observed for two-state folding proteins. However, suc1 forms an intermediate during unfolding and contains considerable residual structure in the denatured state. The stability of the β2–β4 residual structure is surprising, because β4 is the strand involved in domain swapping. This stability suggests that the domain-swapping event, if physiologically relevant, may require the assistance of additional factors in vivo or occur early in the folding process

Implementation of 3D spatial indexing and compression in a large-scale molecular dynamics simulation database for rapid atomic contact detection

<p>Abstract</p> <p>Background</p> <p>Molecular dynamics (MD) simulations offer the ability to observe the dynamics and interactions of both whole macromolecules and individual atoms as a function of time. Taken in context with experimental data, atomic interactions from simulation provide insight into the mechanics of protein folding, dynamics, and function. The calculation of atomic interactions or contacts from an MD trajectory is computationally demanding and the work required grows exponentially with the size of the simulation system. We describe the implementation of a spatial indexing algorithm in our multi-terabyte MD simulation database that significantly reduces the run-time required for discovery of contacts. The approach is applied to the Dynameomics project data. Spatial indexing, also known as spatial hashing, is a method that divides the simulation space into regular sized bins and attributes an index to each bin. Since, the calculation of contacts is widely employed in the simulation field, we also use this as the basis for testing compression of data tables. We investigate the effects of compression of the trajectory coordinate tables with different options of data and index compression within MS SQL SERVER 2008.</p> <p>Results</p> <p>Our implementation of spatial indexing speeds up the calculation of contacts over a 1 nanosecond (ns) simulation window by between 14% and 90% (i.e., 1.2 and 10.3 times faster). For a 'full' simulation trajectory (51 ns) spatial indexing reduces the calculation run-time between 31 and 81% (between 1.4 and 5.3 times faster). Compression resulted in reduced table sizes but resulted in no significant difference in the total execution time for neighbour discovery. The greatest compression (~36%) was achieved using page level compression on both the data and indexes.</p> <p>Conclusions</p> <p>The spatial indexing scheme significantly decreases the time taken to calculate atomic contacts and could be applied to other multidimensional neighbor discovery problems. The speed up enables on-the-fly calculation and visualization of contacts and rapid cross simulation analysis for knowledge discovery. Using page compression for the atomic coordinate tables and indexes saves ~36% of disk space without any significant decrease in calculation time and should be considered for other non-transactional databases in MS SQL SERVER 2008.</p

Synaptic vesicle mimics affect the aggregation of wild-type and A53T α-synuclein variants differently albeit similar membrane affinity

Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected]. α-Synuclein misfolding results in the accumulation of amyloid fibrils in Parkinson\u27s disease. Missense protein mutations (e.g. A53T) have been linked to early onset disease. Although α-synuclein interacts with synaptic vesicles in the brain, it is not clear what role they play in the protein aggregation process. Here, we compare the effect of small unilamellar vesicles (lipid composition similar to synaptic vesicles) on wild-type (WT) and A53T α-synuclein aggregation. Using biophysical techniques, we reveal that binding affinity to the vesicles is similar for the two proteins, and both interact with the helix long axis parallel to the membrane surface. Still, the vesicles affect the aggregation of the variants differently: effects on secondary processes such as fragmentation dominate for WT, whereas for A53T, fibril elongation is mostly affected. We speculate that vesicle interactions with aggregate intermediate species, in addition to monomer binding, vary between WT and A53T, resulting in different consequences for amyloid formation.\ua0\ua9 The Author(s) 2019

J. Mol. (1992) 223. 1121-1138 Molecular Dynamics Simulations of Helix Denaturation

Introduction Motion and structural are important for the biological activity of proteins and, as the most abundant form of secondary structure found in globular proteins. the dvnamics of the a-helix are particularly important. The motion and structural transitions that undergo are also of interest to a variety of other processes including hormone-receptor interactions (Frv et al., the efficacy of drugs, vaccine development, immune function (Tainer et al., 1984; Fieser et membrane fusion and possiblv membrane transport (Vogel et al., 1988). inherent, stability of the is also of interest because of its probable role in protein folding. One of the currently favored models for protein folding, the framework model! postulates that secondary structure is formed early in folding and that these preformed, marginallv stable fragments coalesce to form tertiary structure (Ptitsyn &amp; 1975; Kim Baldwin, 1982). This hypothesis implies that secondary structure should be present under conditions whe