32 research outputs found
On the conservation of the slow conformational dynamics within the amino acid kinase family: NAGK the paradigm
N-Acetyl-L-Glutamate Kinase (NAGK) is the structural paradigm for examining the catalytic mechanisms and dynamics of amino acid kinase family members. Given that the slow conformational dynamics of the NAGK (at the microseconds time scale or slower) may be rate-limiting, it is of importance to assess the mechanisms of the most cooperative modes of motion intrinsically accessible to this enzyme. Here, we present the results from normal mode analysis using an elastic network model representation, which shows that the conformational mechanisms for substrate binding by NAGK strongly correlate with the intrinsic dynamics of the enzyme in the unbound form. We further analyzed the potential mechanisms of allosteric signalling within NAGK using a Markov model for network communication. Comparative analysis of the dynamics of family members strongly suggests that the low-frequency modes of motion and the associated intramolecular couplings that establish signal transduction are highly conserved among family members, in support of the paradigm sequence→structure→dynamics→function © 2010 Marcos et al
Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
Polyglutamine (polyQ) tracts are low-complexity regions and their expansion is linked to certain neurodegenerative diseases. Here the authors combine experimental and computational approaches to find that the length of the androgen receptor polyQ tract correlates with its helicity and show that the polyQ helical structure is stabilized by hydrogen bonds between the Gln side chains and main chain carbonyl groups
Dietary inflammatory index and anthropometric measures of obesity in a population sample at high cardiovascular risk from the PREDIMED (PREvención con DIeta MEDiterránea) trial
The dietary inflammatory index (DII) is a new tool to assess the inflammatory potential of the diet. In the present study, we aimed to determine the association between the DII and BMI, waist circumference and waist:height ratio (WHtR). We conducted a cross-sectional study of 7236 participants recruited into the PREvención con DIeta MEDiterránea trial. Information from a validated 137-item FFQ was used to calculate energy, food and nutrient intakes. A fourteen-item dietary screener was used to assess adherence to the Mediterranean diet (MeDiet). Sex-specific multivariable linear regression models were fitted to estimate differences (and 95 % CI) in BMI, waist circumference and WHtR across the quintiles of the DII. All nutrient intakes, healthy foods and adherence to the MeDiet were higher in the quintile with the lowest DII score (more anti-inflammatory values) except for intakes of animal protein, saturated fat and monounsaturated fat. Although an inverse association between the DII and total energy was apparent, the DII was associated with higher average BMI, waist circumference and WHtR after adjusting for known risk factors. The adjusted difference in the WHtR for women and men between the highest and lowest quintiles of the DII was 1·60 % (95 % CI 0·87, 2·33) and 1·04 % (95 % CI 0·35, 1·74), respectively. Pro-inflammatory scores remained associated with obesity after controlling for the effect that adherence to a MeDiet had on inflammation. In conclusion, the present study shows a direct association between the DII and indices of obesity, and supports the hypothesis that diet may have a role in the development of obesity through inflammatory modulation mechanisms
Changes in Dynamics upon Oligomerization Regulate Substrate Binding and Allostery in Amino Acid Kinase Family Members
Oligomerization is a functional requirement for many proteins. The interfacial interactions and the overall packing geometry of the individual monomers are viewed as important determinants of the thermodynamic stability and allosteric regulation of oligomers. The present study focuses on the role of the interfacial interactions and overall contact topology in the dynamic features acquired in the oligomeric state. To this aim, the collective dynamics of enzymes belonging to the amino acid kinase family both in dimeric and hexameric forms are examined by means of an elastic network model, and the softest collective motions (i.e., lowest frequency or global modes of motions) favored by the overall architecture are analyzed. Notably, the lowest-frequency modes accessible to the individual subunits in the absence of multimerization are conserved to a large extent in the oligomer, suggesting that the oligomer takes advantage of the intrinsic dynamics of the individual monomers. At the same time, oligomerization stiffens the interfacial regions of the monomers and confers new cooperative modes that exploit the rigid-body translational and rotational degrees of freedom of the intact monomers. The present study sheds light on the mechanism of cooperative inhibition of hexameric N-acetyl-L-glutamate kinase by arginine and on the allosteric regulation of UMP kinases. It also highlights the significance of the particular quaternary design in selectively determining the oligomer dynamics congruent with required ligand-binding and allosteric activities
A Transition Path Sampling Study of the Reaction Catalyzed by the Enzyme Chorismate Mutase
Enzymatic Minimum Free Energy Path Calculations Using Swarms of Trajectories
International audienc
Mechanism of the Glycosidic Bond Cleavage of Mismatched Thymine in Human Thymine DNA Glycosylase Revealed by Classical Molecular Dynamics and Quantum Mechanical/Molecular Mechanical Calculations
Base excision of mismatched or damaged
nucleotides catalyzed by
glycosylase enzymes is the first step of the base excision repair
system, a machinery preserving the integrity of DNA. Thymine DNA glycosylase
recognizes and removes mismatched thymine by cleaving the C1′–N1
bond between the base and the sugar ring. Our quantum mechanical/molecular
mechanical calculations of this reaction in human thymine DNA glycosylase
reveal a requirement for a positive charge in the active site to facilitate
C1′–N1 bond scission: protonation of His151 significantly
lowers the free energy barrier for C1′–N1 bond dissociation
compared to the situation with neutral His151. Shuttling a proton
from His151 to the thymine base further reduces the activation free
energy for glycosidic bond cleavage. Classical molecular dynamics
simulations of the H151A mutant suggest that the mutation to the smaller,
neutral, residue increases the water accessibility of the thymine
base, rendering direct proton transfer from the bulk feasible. Quantum
mechanical/molecular mechanical calculations of the glycosidic bond
cleavage reaction in the H151A mutant show that the activation free
energy is slightly lower than in the wild-type enzyme, explaining
the experimentally observed higher reaction rates in this mutant
Neutral Gold(I) Metallosupramolecular Compounds: Synthesis and Characterization, Photophysical Properties, and Density Functional Theory Studies
Enzymatic Minimum Free Energy Path Calculations Using Swarms of Trajectories
The development of approaches for
simulating rare events in complex
molecular systems is a central concern in chemical physics. In recent
work, Roux and co-workers proposed a novel, swarms of trajectories
(SoT) method for determining the transition paths of such events.
It consists of the dynamical refinement on the system’s free
energy surface of a putative transition path that is parametrized
in terms of a set of collective variables (CVs) that are identified
as being important for the transition. In this work, we have implemented
the SoT method and used it to investigate the catalytic mechanisms
of two enzymatic reactions using hybrid QM/MM potentials. Our aim
has been to test the performance of SoT for enzyme systems and to
devise robust simulation protocols that can be employed in future
studies of this type. We identify the conditions under which converged
results can be obtained using inertial and Brownian dynamical evolutions
of the CVs, show that the inclusion of several CVs can give significant
additional insight into the mechanisms of the reactions, and show
that the use of minimum energy paths as starting guesses can greatly
accelerate path refinement