Temperature dependent dynamics of DegP-trimer: A molecular dynamics study

DegP is a heat shock protein from high temperature requirement protease A family, which reacts to the environmental stress conditions in an ATP independent way. The objective of the present analysis emerged from the temperature dependent functional diversity of DegP between chaperonic and protease activities at temperatures below and above 28 °C, respectively. DegP is a multimeric protein and the minimal functional unit, DegP-trimer, is of great importance in understanding the DegP pathway. The structural aspects of DegP-trimer with respect to temperature variation have been studied using molecular dynamics simulations (for 100 ns) and principal component analysis to highlight the temperature dependent dynamics facilitating its functional diversity. The DegP-trimer revealed a pronounced dynamics at both 280 and 320 K, when compared to the dynamics observed at 300 K. The LA loop is identified as the highly flexible region during dynamics and at extreme temperatures, the residues 46–80 of LA loop express a flip towards right (at 280) and left ( at 320 K) with respect to the fixed β-sheet connecting the LA loop of protease for which Phe46 acts as one of the key residues. Such dynamics of LA loop facilitates inter-monomeric interaction with the PDZ1 domain of the neighbouring monomer and explains its active participation when DegP exists as trimer. Hence, the LA loop mediated dynamics of DegP-trimer is expected to provide further insight into the temperature dependent dynamics of DegP towards the understanding of its assembly and functional diversity in the presence of substrate

Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone

BACKGROUND: Complexes of nucleosomes, which often occur in the gene promoter areas, are one of the fundamental levels of chromatin organization and thus are important for transcription regulation. Investigating the dynamic structure of a single nucleosome as well as nucleosome complexes is important for understanding transcription within chromatin. In a previous work, we highlighted the influence of histone variants on the functional dynamics of a single nucleosome using normal mode analysis developed by Bahar et al. The present work further analyzes the dynamics of nucleosome complexes (nucleosome oligomers or oligonucleosomes) such as dimer, trimer and tetramer (beads on a string model) with conventional core histones as well as with the H2A.Z histone variant using normal mode analysis. RESULTS: The global dynamics of oligonucleosomes reveal larger amplitude of motion within the nucleosomes that contain the H2A.Z variant with in-planar and out-of-planar fluctuations as the common mode of relaxation. The docking region of H2A.Z and the L1:L1 interactions between H2A.Z monomers of nucleosome (that are responsible for the highly stable nucleosome containing variant H2A.Z-histone) are highly dynamic throughout the first two dynamic modes. CONCLUSION: Dissection of the dynamics of oligonucleosomes discloses in-plane as well as out-of-plane fluctuations as the common mode of relaxation throughout the global motions. The dynamics of individual nucleosomes and the combination of the relaxation mechanisms expressed by the individual nucleosome are quite interesting and highly dependent on the number of nucleosome fragments present in the complexes. Distortions generated by the non-planar dynamics influence the DNA conformation, and hence the histone-DNA interactions significantly alter the dynamics of the DNA. The variant H2A.Z histone is a major source of weaker intra- and inter-molecular correlations resulting in more disordered motions

Insights into the structural dynamics of Liver kinase B1 (LKB1) by the binding of STe20 Related Adapterα (STRADα) and Mouse protein 25α (MO25α) co-activators

<p>LKB1, the tumour suppressor, is found mutated in Peutz-Jeghers syndrome (PJS). The LKB1 is a serine-threonine kinase protein that is allosterically activated by the binding of STRADα and MO25α without phosphorylating the Thr212 present at activation loop. The present study aims to highlight the structural dynamics and complexation mechanism during the allosteric activation of LKB1 by these co-activators using molecular dynamics simulations. The all atom simulations performed on the complexes of LKB1 with ATP, STRADα, and MO25α for a period of 30 ns reveal that binding of STRADα and MO25α significantly stabilizes the highly flexible regions of LKB1 such as ATP binding region (β1-β2 loop), catalytic & activation loop segments and αG helix. Also, binding of STRADα and MO25α to LKB1 promotes coordinated motion between N- and C-lobes along with the catalytic & activation loops by forming H-bonds between LKB1 and co-activators, which further facilitate to establish the conserved attributes of active LKB1 such as (i) formation of salt bridge between Lys78 and Glu98, (ii) formation of stable hydrophobic R- and C-spines, and (iii) interaction between both catalytic and activation loops. Especially, the residues of LKB1 interacting with STRADα (Arg74, Glu342) and MO25α (Glu165, Pro203 and Phe204) are observed to play a significant role in stabilizing the (LKB1-ATP)-(STRADα-ATP)-MO25α complex. Overall, the present work highlighting the structural dynamics of LKB1 by the binding of allosteric co-activators is expected to provide a basic understanding on drug design specific to PJS syndrome.</p

Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone-2

<p><b>Copyright information:</b></p><p>Taken from "Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone"</p><p>http://www.biomedcentral.com/1472-6807/7/76</p><p>BMC Structural Biology 2007;7():76-76.</p><p>Published online 8 Nov 2007</p><p>PMCID:PMC2216022.</p><p></p>al modes. The amplitude of fluctuation is graded from black to red (i.e., from the rigid to the flexible domains, respectively). For an easy understanding, the closest view of the color coded monomeric histone tetramer of the left side nucleosome in dimer in the first global mode is shown (middle) in the subdiagram and the secondary structures of the four histones (H3, H4, H2A.Z and H2B) are labeled individually

Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone-10

<p><b>Copyright information:</b></p><p>Taken from "Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone"</p><p>http://www.biomedcentral.com/1472-6807/7/76</p><p>BMC Structural Biology 2007;7():76-76.</p><p>Published online 8 Nov 2007</p><p>PMCID:PMC2216022.</p><p></p>ond nucleosomes in dimer (I), (II) and (III) crystal structures; the amplitude of interactions follow the same color coding as Figure 2

The proteinopathy of D169G and K263E mutants at the RNA Recognition Motif (RRM) domain of tar DNA-binding protein (tdp43) causing neurological disorders: A computational study

<p>One of the multitasking proteins, transactive response DNA-binding protein 43 (tdp43) plays a key role in RNA regulation and the two pathogenic mutations such as D169G and K263E, located at the RNA Recognition Motif (RRM) of tdp43, are reported to cause neurological disorders such as Amyotrophic Lateral Sclerosis and FrontoTemporal Lobar Degeneration. As the exploration of the proteinopathy demands both structural and functional characterizations of mutants, a comparative analysis on the wild type and mutant tdp43 (D169G and K263E) and their complexes with RNA has been performed using computational approaches. Molecular dynamics simulations revealed comparatively stable mutant structures compared to wild type tdp43. Both mutants show lesser binding affinity toward RNA molecule when compared to the wild type tdp43. Some of the observed features, including the increased solvent-accessible surface area, conformational flexibility as well as unfolding of tdp43, and the altered RNA conformation in tp43-RNA complex, reveal the susceptibility of these mutants to induce conformational changes in tdp43 for a possible aggregation in the cytoplasm. Particularly, the enhanced aggregation propensity of both mutants also evidences the higher probability of cytoplasmic aggregation of tdp43 mutants. Hence, the present analysis highlighting the structural and functional aspects of wild and mutant tdp43 will form the basis to gain insight into the proteinopathy of tdp43 and the related structure-based drug discovery. Thus, tdp43 can be used as target to develop novel therapeutic approaches or drug designing.</p

Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone-9

<p><b>Copyright information:</b></p><p>Taken from "Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone"</p><p>http://www.biomedcentral.com/1472-6807/7/76</p><p>BMC Structural Biology 2007;7():76-76.</p><p>Published online 8 Nov 2007</p><p>PMCID:PMC2216022.</p><p></p>rst nucleosomes in dimer (I), (II) and (III) crystal structures. The uncorrelated regions (colored black) separate the correlated (where the amplitude increases from blue to red) and anti-correlated regions (colored cyan)

Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone-3

<p><b>Copyright information:</b></p><p>Taken from "Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone"</p><p>http://www.biomedcentral.com/1472-6807/7/76</p><p>BMC Structural Biology 2007;7():76-76.</p><p>Published online 8 Nov 2007</p><p>PMCID:PMC2216022.</p><p></p>lobal modes

Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone-8

<p><b>Copyright information:</b></p><p>Taken from "Global dynamics of newly constructed oligonucleosomes of conventional and variant H2A.Z histone"</p><p>http://www.biomedcentral.com/1472-6807/7/76</p><p>BMC Structural Biology 2007;7():76-76.</p><p>Published online 8 Nov 2007</p><p>PMCID:PMC2216022.</p><p></p> vector from the anisotropic fluctuation to the crystal coordinates for the tetramer as shown in the front and right side view in the first slowest mode