37 research outputs found
Simulation, Experiment, and Evolution: Understanding Nucleation in Protein S6 Folding
In this study, we explore nucleation and the transition state ensemble of the
ribosomal protein S6 using a Monte Carlo Go model in conjunction with
restraints from experiment. The results are analyzed in the context of
extensive experimental and evolutionary data. The roles of individual residues
in the folding nucleus are identified and the order of events in the S6 folding
mechanism is explored in detail. Interpretation of our results agrees with, and
extends the utility of, experiments that shift f-values by modulating
denaturant concentration and presents strong evidence for the realism of the
mechanistic details in our Monte Carlo Go model and the structural
interpretation of experimental f-values. We also observe plasticity in the
contacts of the hydrophobic core that support the specific nucleus. For S6,
which binds to RNA and protein after folding, this plasticity may result from
the conformational flexibility required to achieve biological function. These
results present a theoretical and conceptual picture that is relevant in
understanding the mechanism of nucleation in protein folding.Comment: PNAS in pres
Phi-values in protein folding kinetics have energetic and structural components
Phi-values are experimental measures of how the kinetics of protein folding
is changed by single-site mutations. Phi-values measure energetic quantities,
but are often interpreted in terms of the structures of the transition state
ensemble. Here we describe a simple analytical model of the folding kinetics in
terms of the formation of protein substructures. The model shows that
Phi-values have both structural and energetic components. In addition, it
provides a natural and general interpretation of "nonclassical" Phi-values
(i.e., less than zero, or greater than one). The model reproduces the
Phi-values for 20 single-residue mutations in the alpha-helix of the protein
CI2, including several nonclassical Phi-values, in good agreement with
experiments.Comment: 15 pages, 3 figures, 1 tabl
Polymorphisms on PAI-1 and ACE genes in association with fibrinolytic bleeding after on-pump cardiac surgery
Publisher Copyright: © 2015 Ozolina et al.Background: Carriers of plasminogen activator inhibitor -1 (PAI-1) -675 genotype 5G/5G may be associated with lower preoperative PAI-1 plasma levels and higher blood loss after heart surgery using cardiopulmonary bypass (CPB). We speculate if polymorphisms of PAI-1 -844 A/G and angiotensin converting enzyme (ACE) intron 16 I/D also might promote fibrinolysis and increase postoperative bleeding. Methods: We assessed PAI-1 -844 A/G, and ACE intron 16 I/D polymorphisms by polymerase chain reaction technique and direct sequencing of genomic DNA from 83 open heart surgery patients that we have presented earlier. As primary outcome, accumulated chest tube drainage (CTD) at 4 and 24 h were analyzed for association with genetic polymorphisms. As secondary outcome, differences in plasma levels of PAI-1, t-PA/PAI-1 complex and D-dimer were determined for each polymorphism. SPSS® was used for statistical evaluation. Results: The lowest preoperative PAI-1 plasma levels were associated with PAI-1 -844 genotype G/G, and higher CTD, as compared with genotype A/A at 4 and 24 h after surgery. Correspondingly, 4 h after the surgery CTD was higher in carriers of ACE intron 16 genotype I/I, as compared with genotype D/D. PAI-1 plasma levels and t-PA/PAI-1 complex reached nadir in carriers of ACE intron 16 genotype I/I, in whom we also noticed the highest D-dimer levels immediately after surgery. Notably, carriers of PAI-1 -844 genotype G/G displayed higher D-dimer levels at 24 h after surgery as compared with those of genotype A/G. Conclusions: Increased postoperative blood loss secondary to enhanced fibrinolysis was associated with carriers of PAI-1 -844 G/G and ACE Intron 16 I/I, suggesting that these genotypes might predict increased postoperative blood loss after cardiac surgery using CPB.publishersversionPeer reviewe
Acquired and congenital disorders of sung performance: A review.
Many believe that the majority of people are unable to carry a tune. Yet, this
widespread idea underestimates the singing abilities of the layman. Most
occasional singers can sing in tune and in time, provided that they perform at a
slow tempo. Here we characterize proficient singing in the general population
and identify its neuronal underpinnings by reviewing behavioral and neuroimaging
studies. In addition, poor singing resulting from a brain injury or neurogenetic
disorder (i.e., tone deafness or congenital amusia) is examined. Different lines
of evidence converge in indicating that poor singing is not a monolithic
deficit. A variety of poor-singing "phenotypes" are described,
with or without concurrent perceptual deficits. In addition, particular
attention is paid to the dissociations between specific abilities in poor
singers (e.g., production of absolute vs. relative pitch, pitch vs. time
accuracy). Such diversity of impairments in poor singers can be traced to
different faulty mechanisms within the vocal sensorimotor loop, such as pitch
perception and sensorimotor integration