23,006 research outputs found
End-to-End Optimized Pipeline for Prediction of Protein Folding Kinetics
Protein folding is the intricate process by which a linear sequence of amino
acids self-assembles into a unique three-dimensional structure. Protein folding
kinetics is the study of pathways and time-dependent mechanisms a protein
undergoes when it folds. Understanding protein kinetics is essential as a
protein needs to fold correctly for it to perform its biological functions
optimally, and a misfolded protein can sometimes be contorted into shapes that
are not ideal for a cellular environment giving rise to many degenerative,
neuro-degenerative disorders and amyloid diseases. Monitoring at-risk
individuals and detecting protein discrepancies in a protein's folding kinetics
at the early stages could majorly result in public health benefits, as
preventive measures can be taken. This research proposes an efficient pipeline
for predicting protein folding kinetics with high accuracy and low memory
footprint. The deployed machine learning (ML) model outperformed the
state-of-the-art ML models by 4.8% in terms of accuracy while consuming 327x
lesser memory and being 7.3% faster.Comment: Accepted for presentation at the 22nd International Conference on
Machine Learning and Application
Discrete Kinetic Models from Funneled Energy Landscape Simulations
A general method for facilitating the interpretation of computer simulations of protein folding with minimally frustrated energy landscapes is detailed and applied to a designed ankyrin repeat protein (4ANK). In the method, groups of residues are assigned to foldons and these foldons are used to map the conformational space of the protein onto a set of discrete macrobasins. The free energies of the individual macrobasins are then calculated, informing practical kinetic analysis. Two simple assumptions about the universality of the rate for downhill transitions between macrobasins and the natural local connectivity between macrobasins lead to a scheme for predicting overall folding and unfolding rates, generating chevron plots under varying thermodynamic conditions, and inferring dominant kinetic folding pathways. To illustrate the approach, free energies of macrobasins were calculated from biased simulations of a non-additive structure-based model using two structurally motivated foldon definitions at the full and half ankyrin repeat resolutions. The calculated chevrons have features consistent with those measured in stopped flow chemical denaturation experiments. The dominant inferred folding pathway has an “inside-out”, nucleation-propagation like character
Transition states in protein folding kinetics: Modeling Phi-values of small beta-sheet proteins
Small single-domain proteins often exhibit only a single free-energy barrier,
or transition state, between the denatured and the native state. The folding
kinetics of these proteins is usually explored via mutational analysis. A
central question is which structural information on the transition state can be
derived from the mutational data. In this article, we model and structurally
interpret mutational Phi-values for two small beta-sheet proteins, the PIN and
the FBP WW domain. The native structure of these WW domains comprises two
beta-hairpins that form a three-stranded beta-sheet. In our model, we assume
that the transition state consists of two conformations in which either one of
the hairpins is formed. Such a transition state has been recently observed in
Molecular Dynamics folding-unfolding simulations of a small designed
three-stranded beta-sheet protein. We obtain good agreement with the
experimental data (i) by splitting up the mutation-induced free-energy changes
into terms for the two hairpins and for the small hydrophobic core of the
proteins, and (ii) by fitting a single parameter, the relative degree to which
hairpin 1 and 2 are formed in the transition state. The model helps to
understand how mutations affect the folding kinetics of WW domains, and
captures also negative Phi-values that have been difficult to interpret.Comment: 27 pages, 6 pages, 3 tables; to appear in Biophys.
Loop-closure principles in protein folding
Simple theoretical concepts and models have been helpful to understand the
folding rates and routes of single-domain proteins. As reviewed in this
article, a physical principle that appears to underly these models is loop
closure.Comment: 27 pages, 5 figures; to appear in Archives of Biochemistry and
Biophysic
Are structural biases at protein termini a signature of vectorial folding?
Experimental investigations of the biosynthesis of a number of proteins have
pointed out that part of the native structure can be acquired already during
translation. We carried out a comprehensive statistical analysis of some
average structural properties of proteins that have been put forward as
possible signatures of this progressive buildup process. Contrary to a
widespread belief, it is found that there is no major propensity of the amino
acids to form contacts with residues that are closer to the N terminus.
Moreover, it is found that the C terminus is significantly more compact and
locally-organized than the N one. Also this bias, though, is unlikely to be
related to vectorial effects, since it correlates with subtle differences in
the primary sequence. These findings indicate that even if proteins aquire
their structure vectorially no signature of this seems to be detectable in
their average structural properties.Comment: 7 pages, 3 figures, 1 tabl
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