10^th International Congress on Structural Biology October 18-19, 2018 Helsinki, Finland

Biography:

Abstract:

Parkinson’s disease is caused by disruption of cells which provide dopamine to the striatum in the brain. Therefore, the main approach made for treatment of the disease has based on increasing dopaminergic signaling by using dopamine agonists, preventing dopamine breakdown via monoamine oxidase enzymes or supplying additional dopamine in the form of L-dopa. Even though L-dopa is known as the most effective drug so far, its efficacy decreases with time due to the use of high dosage of the drug. Moreover, it also causes motor complications such as motor fluctuations and dyskinesia. In this multidisciplinary project, we have aimed for developing hetero-bivalent ligands that target A2AR (Adenosine-2A-receptor)-D2R (Dopamine-2receptor) hetero-tetramer, which has been shown to be the dominant stoichiometry of A2AR-D2R. Firstly, we design and dock hetero-bivalent ligands to the receptors and investigate the molecular mechanism of allosteric interactions within the heterotetramer by means of accelerated molecular dynamics simulations. Subsequently, successful drug candidates are synthesized and tested in vitro for their activities. More importantly, the drug candidates are also tested by in silico and in vitro models for their permeation against blood-brain barrier. So far, hetero-bivalent ligands have been only used as molecular tools for detecting the existence of the receptor dimers. On the other hand, the current study will provide a chance to test the capability of hetero-bivalent ligands for being used as therapeutic molecules. In this way, we expect to develop more effective therapeutic molecules to alleviate the symptoms of Parkinson’s disease hence increasing the quality of patient’s life

Biography:

Abstract:

Parkinson’s disease is caused by disruption of cells which provide dopamine to the striatum in the brain. Therefore, the main approach made for treatment of the disease has based on increasing dopaminergic signaling by using dopamine agonists, preventing dopamine breakdown via monoamine oxidase enzymes or supplying additional dopamine in the form of L-dopa. Even though L-dopa is known as the most effective drug so far, its efficacy decreases with time due to the use of high dosage of the drug. Moreover, it also causes motor complications such as motor fluctuations and dyskinesia. In this multidisciplinary project, we have aimed for developing hetero-bivalent ligands that target A2AR (Adenosine-2A-receptor)-D2R (Dopamine-2receptor) hetero-tetramer, which has been shown to be the dominant stoichiometry of A2AR-D2R. Firstly, we design and dock hetero-bivalent ligands to the receptors and investigate the molecular mechanism of allosteric interactions within the heterotetramer by means of accelerated molecular dynamics simulations. Subsequently, successful drug candidates are synthesized and tested in vitro for their activities. More importantly, the drug candidates are also tested by in silico and in vitro models for their permeation against blood-brain barrier. So far, hetero-bivalent ligands have been only used as molecular tools for detecting the existence of the receptor dimers. On the other hand, the current study will provide a chance to test the capability of hetero-bivalent ligands for being used as therapeutic molecules. In this way, we expect to develop more effective therapeutic molecules to alleviate the symptoms of Parkinson’s disease hence increasing the quality of patient’s life

Biography:

Meriem El Ghachi has completed her PhD from Paris University of Paris-Sud, France. He is a Post-doctorate at University of Liege, Belgium. She has published 17 papers in reputed journals.

Abstract:

Undecaprenyl-phosphate C55-P is a key lipid carrier of glycan intermediate required for the synthesis of a variety of cell wall polymers such as Peptidoglycan (PG), Lipopolysaccharides (LPS) O-antigen wall teichoic acids, capsular polysaccharide, common enterobacterial antigen, membrane-derivative oligosaccharides and exopolysaccharides. In bacteria, during peptidoglycan synthesis, the phospho-N-acetylmuramoyl (-pentapeptide) -N-acetyl glucosamine is the essential motif carried by the C55-P. The resulting lipid, C55-PP-MurNAc-(pentatpetide)-GlucNAc (lipid II), is translocated towards the periplasmic side by several putative flippases. The MurNAc-(pentatpetide)-GlucNAc is added to the elongating chains of PG and C55- P is released as C55- PP. This precursor is also provided by the de novo synthesis in the cytosol that is catalyzed by a Cis-Prenyl Pyrophosphate Synthase, UPPS, which successively adds eight isoprene units from C5-PP on farnesyl pyrophosphate. Two families of phosphatases can perform the subsequent dephosphorylation of C55-PP into C55-P, common to the in vitro synthesis and carrier lipid recycling. In E. coli, 1 BacA and 3 phosphatidic acid phosphatases 2 (PgpB, YbjG and LpxT), active on C55-PP have been identified. PgpB being also involved in the phosphatidyl glycerol metabolism and LpxT transferring the phosphate from C55-PP to lipid A. Whereas Bacillus subtilis has three C55-PP phosphatases 1 BacA (YubB) and 2 phosphatidic acid phosphatases 2 (YwoA and YodM). We obtained the structure of BacA using lipidic cubic phase method. The crystal structure at 2.6 A revealed an unexpected fold according to the previous biochemical studies. Moreover, we solved the structure of bsPgpB (yodM) in the presence and absence of its favorite substrate, phosphatidyl glycerol. 

Biography:

Abstract:

Biography:

Sushil Tripathi is a postdoctoral researcher in University of Helsinki. He had completed his PhD from Norwegian University of Science and Technology, Norway. 

Abstract:

Biography:

Maryam Alobathani has completed her Bachelor studies in Biotechnology by age 22 from University of Sharjah and know she’s working as a laboratory supervisor and completing her Master studies at the same university.

Abstract:

Deafness is a disease of inability to hear referred as hear impairment or anacusis for those with low or no hearing. It’s important at all levels of health care due to their significant burden on affected individuals and societies. Hearing loss can be classified as partial or completely inability to hear. Deafness can occur due to different mutations in different human genome such as Connexin26 the most common deafness gene, CDH23, TMC1 and in mitochondria. mitochondrial organelle is ubiquitous in eukaryotic as intracellular double membrane structure. The main function of mitochondria is to synthesis ATP by OXPHS and plays important roles in cell death and oxidative stress control. Mutation in mitochondrial DNA cause OXPHS defects that leads to many diseases one of them is hearing loss as syndromic and non-syndromic deafness. Therefore, we aim in this research to identify the genetic causes of NSAHL underlying wide spectrum of congenital conditions in UAE population. This study focused on a non-syndromic deafness caused by mutation on a mitochondrial MTRNR1 gene that encodes 12SrRNA. 40 Samples were collected from unrelated NSHL UAE family members and screened using biological tools such as PCR, Genomic sequencing machines and Bioinformatics tools. Expert geneticist recruiting and clinically assessing the participant patients involved in this study.The main approaches proposed are: (i) homozygosity maps were used to localize the homozygous regions in each particular family, (ii) next generation sequencing platform used to sequence the whole-exome of an affected individuals to explore all variants including the pathogenic mutations, finally (iii) pathogenicity of the outcoming variant results validated or ruled out by performing functional assays. The study indicates two out of the total 40 samples of unrelated UAE families with deafness due to mitochondrial 12S rRNA mutation m.669 T>C and m.827A>G, as well some known polymorphisms. This study is part of other researches done on a larger scale on similar area of interest that will reach to figure out new mutation related to mtDNA 12S rRNA variations. This finding can also help in future genetic counselling, prenatal screening, and post-natal genetic diagnosis to prevent the prevalence of more NSHL patients.

Biography:

T V Koshlan is currently working as a Professor at Peter the Great St. Petersburg Polytechnic University, Institute of Applied Mathematics and Mechanics, Department of Higher Mathematics. He has completed his PhD in Physics and Mathematics with Mathematical modeling of the optical properties of multilayer biological systems and structures in their heterogeneous conjugation. He has habilitation at the State Polytechnic University of St. Petersburg, Russia. His research interests are diffraction theory, electrodynamics, physics of lasers, tissue optical methods of mathematical modeling in biological tissue optics and numerical method, biophysics.

Abstract:

In this report, two algorithms are developed, algorithm 1 and algorithm 2. Algorithm 1 was developed in order to search for the interaction of a polypeptide chain of a full-length protein with short active region. Algorithm 2 was developed to determine the most active sites of interaction between full-length proteins when dimers are formed in the direction from the N terminus to C terminus. Numerical calculations were made using proteins Mdm2, Nap1, P53. For modern proteomics, research and prediction of protein interactions are very important tasks, since they determine the function of proteins at levels from the cell to the whole organism. For proteins whose structure is known, the search for intermolecular interactions according to known data on the conformation of their tertiary structure reduces to the problem of searching for geometric complementarity of the sections of two interacting molecular surfaces and modeling their contacts, the so-called molecular docking. The task of molecular docking is the task of a conformational search algorithm, which reduces to a search for the conformational space of the formed biological complex due to the variation of the torsion angles of protein molecules. Modern conformational search algorithms in most cases find conformations that are generally close to the experimentally found structures in a relatively short time. However, there are factors that also have a significant impact on the success of the docking, which are often not taken into account in standard algorithms. One such factor is the conformational mobility of the target protein. The mobility range can be different beginning with a small adjustment of the side chains and ending with scale domain movements. These movements play an important role. At first glance, the most logical solution to this problem is to take into account the mobility of the protein in a docking program. Unfortunately, modern computational tools do not allow such modeling to be performed in an acceptable time frame since a protein molecule is very large, and allowing for mobility over all degrees of freedom can lead to a so-called combinatorial explosion (an astronomical increase in the number of possible variants). Only in some programs is there a limited mobility of protein binding sites (usually at the level of a small adaptation of conformations of the side chains of the active center residues). Another approach to this problem consists in docking the same protein in several different conformations and then selecting the best solutions from each docking run. The third approach is to find a universal structure of the target protein in which docking would produce fairly good results for different classes of ligands. In this case, the number of missed (but correct) solutions decreases, but the number of incorrect options also increases significantly. It should also be noted that most programs for the theoretical docking of proteins work according to the following principle: one protein is fixed in space, and the second is rotated around it in a variety of ways. At the same time, for each rotation configuration, estimates are made for the evaluation function. The evaluation function is based on surface complementarity (the mutual correspondence of complementary structures (macromolecules, radicals), determined by their chemical properties), electrostatic interactions, van der Waals repulsion and so on. The problem with this approach is that calculations throughout the configuration space require a lot of time, rarely leading to a single solution, which in turn does not allow us to speak of the uniqueness of the target protein and ligand interaction variant. So in the work while modeling by the methods of molecular dynamics, from 200 to 10 000 possible combinations of the formation of a protein complex with a ligand were found. Such a large number of modifications, along with the lack of a criterion for selecting the most probable variants of the bound structures of biological complexes (which would allow a radical reduction in their number) makes it very difficult to interpret the theoretical results obtained for practical use, namely, the finding of catalytic centers and a qualitative assessment of the dissociation constant of interacting substances. In contrast to the above computer simulation algorithms, mathematical algorithms have been developed in this chapter that allow determining the detection of proteins active regions and detecting the stability of different regions of protein complexes (linear docking) by analyzing the potential energy matrix of pairwise electrostatic interaction between different sites of the biological complex, such as the homodimer of the histone chaperone Nap1-Nap1, the heterodimer of the p53 Mdm2 proteins, and the homodimer Mdm2 Mdm2, which are responsible for the entry of a whole protein molecule into biochemical reactions.

Biography:

Abstract:

Biography:

Abstract:

Here we propose a set of computational resources to inform experiments and facilitate drug discovery against Mycobacterium spp. Mycobacteria are etiological agents of some of the most notorious hazards to public health-tuberculosis (M. tuberculosis) and leprosy (M. leprae). They are also responsible for opportunistic infections in Cystic Fibrosis (CF) patients (M. abscessus). Finally, they are conjectured to be the underlying cause of ulcerative colitis and Crohn’s disease (M. avium subsp. paratuberculosis). Despite their importance for public health, there are very few successful treatment strategies against Mycobacteria, due to their intrinsic resistance to antimicrobials, as well as inherent experimental difficulties in testing drug candidates in vitro. Our resources (CHOPIN: M. tuberculosis, MABELLINI: M. abscessus, HANSEN: M. leprae) provide comprehensive set of high-confidence structural models for the entire bacterial proteome. Models are generated using Vivace pipeline, using Fugue for template identification and Modeller for model building-both developed in-house. On contrary to typical protein structure prediction approaches (e.g. I-TASSER or HHpred), our approach aims to produce models that inform experiments and not necessarily maximize the stereo chemical quality and superposition to crystal structure. As our models are not over-optimized, they can be readily used for analysis of drug ability, effects of mutations and assessing interactions. By combining the results of state-of-art methods developed locally, with comprehensive survey of local and publicly available experimental results, CHOPIN, MABELLINI and HANSEN form resources of unprecedented utility-delivering results of rigorous computational analysis in a user-friendly, approachable and understandable way. The resources are free to use, constantly updated and produced in close collaboration with mycobacterial research community. All the software developed and used is open source and all the data is open access. 

Biography:

Abstract:

Biography:

Abstract:

Biography:

Abstract:

Enterotoxigenic Escherichia coli (ETEC) are responsible for a high diarrheal disease burden, especially in children living in endemic countries and travelers visiting those countries. After oro-fecal transmission, ETEC reaches the small intestine where adhesion occurs through colonization factors. Then heat Labile Toxin (LT), one of the two enterotoxins produced by ETEC, is secreted and causes aqueous diarrhea. LT consists of five B sub-units, which are able to bind the monosialoganglioside GM1 and a single, catalytically-active A subunit stimulating the intracellular synthesis of cyclic Adenosine Monophosphate (cAMP), leading ultimately to fluid and electrolyte secretions into the intestinal lumen. Herein we characterized various purified forms of LT: (1) recombinant B subunit of LT (rLTB) (2) native LT purified from ETEC strain (nLT) and (3) recombinant LT purified from E. coli expressing the protein (rLT). SDS-PAGE analysis showed a difference of migration between the different LT forms confirmed by liquid chromatography coupled to MS (mass shift of 162 Da). This modification was found to be due to the glycation of LT subunits by galactose, a reducing sugar that is used in the LT purification process and remains present during the LT Lyophilization process. This observation has to be taken into account for the purification and storage of LT. Experiments are ongoing to determine if LT glycation could have an impact on the functional activity of LT using an in vitro assay based on cAMP release by epithelial cell line.