1,721,045 research outputs found
On the activation and deactivation pathways of the Lck kinase domain: a computational study
No full textHere we report the description of the conformational pathways connecting the Lck active and inactive states by means of all-atoms molecular dynamics simulations coupled to an enhancing sampling methodology. By such an approach, we describe the major structural determinants characterizing these large conformational transitions and compare such pathways to those obtained for a similar kinase, i.e. c-Src. Our results show that both the activation and deactivation processes could follow distinct pathways, differentiated by the order by which the A-loop and the C-helix regions rearrange
Theoretical Insights into MutY Glycosylase DNA Repair Mechanism
No full textMaintaining the integrity of the genome is fundamental to living organisms. To this end, nature developed several mechanisms to find and promptly repair DNA lesions. Among them, base excision repair (BER) enzymes evolved to efficiently carry out this task. Notably, the mechanisms allowing these proteins to search for, detect, and fix DNA damage on a biologically relevant time scale still remain partially unclear. By taking MutY, a BER enzyme implied in the repair of the 8-oxoguanine–adenine mismatches, as a model system, we shed some light on the repair mechanism through a theoretical-computational approach. First, we estimated the effect of the oxidation state of the MutY iron–sulfur cluster on the protein–DNA binding. Then, the redox thermodynamics of both the protein cluster and DNA nucleobases are calculated. Finally, the charge migration kinetics along the double strand bound to the enzyme has been evaluated. The rationalization of our results indicates that the search for DNA lesions is essentially dictated by the redox chemistry of the species involved, i.e., the iron–sulfur redox cofactor and the DNA bound to the enzyme
The Full Model of the pMHC-TCR-CD3 Complex: A Structural and Dynamical Characterization of Bound and Unbound States
Full text linkThe machinery involved in cytotoxic T-cell activation requires three main characters: the major histocompatibility complex class I (MHC I) bound to the peptide (p), the T-cell receptor (TCR), and the CD3 complex, a multidimer interfaced with the intracellular side. The pMHC:TCR interaction has been largely studied by means of both experimental and computational models, giving a contribution in understanding the complexity of the TCR triggering. Nevertheless, a detailed study of the structural and dynamical characterization of the full complex (pMHC:TCR:CD3 complex) is still missing due to a lack of structural information of the CD3-chains arrangement around the TCR. Very recently, the determination of the TCR:CD3 complex structure by means of Cryo-EM technique has given a chance to build the entire system essential in the activation of T-cells, a fundamental mechanism in the adaptive immune response. Here, we present the first complete model of the pMHC interacting with the TCR:CD3 complex, built in a lipid environment. To describe the conformational behavior associated with the unbound and the bound states, all-atom Molecular Dynamics simulations were performed for the TCR:CD3 complex and for two pMHC:TCR:CD3 complex systems, bound to two different peptides. Our data point out that a conformational change affecting the TCR Constant β (Cβ) region occurs after the binding to the pMHC, revealing a key role of this region in the propagation of the signal. Moreover, we found that TCR reduces the flexibility of the MHC I binding groove, confirming our previous results
Theoretical Characterization of the Dynamical Behavior and Transport Properties of alpha,gamma-Peptide Nanotubes in Solution
No full textWe present here a molecular dynamics study on a promising class of peptide nanotubes with a partially hydrophobic inner cavity and an easy chemical functionalization of the lumen of the cylindrical structure. The structural and dynamical behavior of the nanotube in water, methanol, and chloroform has been analyzed using state of the art theoretical methods. The nanotube structure is always well preserved, but solvent-dependent dynamic alterations are evident. Such dynamic effects are surprisingly more severe in the most viscous solvent (water), as a consequence of the competition in polar solvents between intra- and intermolecular hydrogen bonds. Stiffness analysis from the collected trajectories helped us to characterize the equilibrium deformability of the nanotube, while steered dynamics simulations were used to determine the magnitude of free energy associated with nanotube growth. Analysis of the carrier and permeation properties of the compounds reveals surprising properties: (i) permeability for the most polar solvent (water), (ii) carrier properties for the most apolar solvent (chloroform), and (iii) neither good permeation nor carrier properties for the intermediate solvent in polarity (methanol). Results reported here constitute the most extensive characterization of these nanotubes presented to date and open many intriguing questions on their stability, dynamics, and transport/carrier properties
Rationalizing Sequence and Conformational Effects on the Guanine Oxidation in Different DNA Conformations
Full text link[Image: see text] The effect of the environment on the guanine redox potential is studied by means of a theoretical–computational approach. Our data, in agreement with previous experimental findings, clearly show that the presence of consecutive guanine bases in both single- and double-stranded DNA oligomers lowers their reduction potential. Such an effect is even more marked when a G-rich quadruplex is considered, where the oxidized form of guanine is particularly stabilized. To the best of our knowledge, this is the first computational study reporting on a quantitative estimate of the dependence of the guanine redox potential on sequence and conformational effects in complex DNA molecules, ranging from single-stranded DNA to G-quadruplex
Comparing the efficiency of biased and unbiased molecular dynamics in reconstructing the free energy landscape of Met-enkephalin
No full textAll-atom unbiased molecular dynamics simulations are now able to explore the microsecond to millisecond time scale for simple biological macromolecules in an explicit solvent. This allows for a careful comparison of the efficiency and accuracy of enhanced sampling methods versus long unbiased molecular dynamics in reconstructing conformational free energy surfaces. Here, we use an equilibrium microsecond-long molecular dynamics simulation as a reference to analyze the convergence properties of well-tempered metadynamics with two different sets of collective variables. In the case of the small and very diffusive Met-enkephalin pentapeptide, we find that the performance strongly depends on the choice of the collective variables (CVs). Using a set of principal component analysis derived eigenvectors, the convergence of the FES is faster than with both hand-picked CVs and unbiased molecular dynamics
Density discriminates between thermophilic and mesophilic proteins
No full textDespite an intense interest and a remarkable number of studies on the subject, the relationships between thermostability and (primary, secondary and tertiary) structure of proteins are still not fully understood. Here, comparing the protein density - defined by the ratio between the residue number and protein excluded volume - for a set of thermophilic/mesophilic pairs, we provide evidence that this property is connected to the optimal growth temperature. In particular, our results indicate that thermophilic proteins have - in general - a lower density with respect to the mesophilic counterparts, being such a correlation more pronounced for optimal growth temperature differences greater than 40° C. The effect of the protein thermostability changes on the molecular shape is also presented
Atomic-Level View of the Functional Transition in Vertebrate Hemoglobins: The Case of Antarctic Fish Hbs
No full text[Image: see text] Tetrameric hemoglobins (Hbs) are prototypal systems for studies aimed at unveiling basic structure–function relationships as well as investigating the molecular/structural basis of adaptation of living organisms to extreme conditions. However, a chronological analysis of decade-long studies conducted on Hbs is illuminating on the difficulties associated with the attempts of gaining functional insights from static structures. Here, we applied molecular dynamics (MD) simulations to explore the functional transition from the T to the R state of the hemoglobin of the Antarctic fish Trematomus bernacchii (HbTb). Our study clearly demonstrates the ability of the MD technique to accurately describe the transition of HbTb from the T to R-like states, as shown by a number of global and local structural indicators. A comparative analysis of the structural states that HbTb assumes in the simulations with those detected in previous MD analyses conducted on HbA (human Hb) highlights interesting analogies (similarity of the transition pathway) and differences (distinct population of intermediate states). In particular, the ability of HbTb to significantly populate intermediate states along the functional pathway explains the observed propensity of this protein to assume these structures in the crystalline state. It also explains some functional data reported on the protein that indicate the occurrence of other functional states in addition to the canonical R and T ones. These findings are in line with the emerging idea that the classical two-state view underlying tetrameric Hb functionality is probably an oversimplification and that other structural states play important roles in these proteins. The ability of MD simulations to accurately describe the functional pathway in tetrameric Hbs suggests that this approach may be effectively applied to unravel the molecular and structural basis of Hbs exhibiting peculiar functional properties as a consequence of the environmental adaptation of the host organism
Theoretical calculation of the pyrene emission properties in different solvents
No full textDue to its high quantum yield and long fluorescence lifetime, pyrene molecule is a widely used fluorescence probe. From a theoretical–computational viewpoint, the modeling of its emission properties in different environments still represents a challenge, mainly because the coupling with the environment severely affects its emission behavior. We employed our computational–theoretical approach to quantitatively model the pyrene emission, which combines quantum chemical calculations with all-atom molecular dynamics simulations. Our calculated fluorescence properties, well matching the experimental data, highlight that even slight geometrical fluctuations of pyrene at room temperature can provide relevant effects on its radiative lifetime
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