Bioinformatics amd Molecular Modelling - Assignment Example

Introduction This paper is examining Hepatitis C virus and other information that is relevant to bioinformaticians. It analyses the NS3, protein data bank, the target can website among other issues of molecular biology. It is structured in question form, therefore, at every aspect the paper will try to answer and elaborate on the answers given. Hepatitis C virus is a diverse positive stranded genetic RNA virus that infects an estimated 170 million people across the world. It is categorized into a diversified 6 major genotypes and further into numerous subtypes with different distributions (geographical). The first to the 3rd genotype prevail more across the world as compared to the rest of HCV genotypes. Infection by HCV is the leading cause of chronic liver infection that after ages or decades becomes liver cirrhosis, failure, or cancer. Protein Data Bank The Protein Data Bank (PDB) is a source for the 3-D structural data of large biological molecules, like nucleic acids and proteins. 1tnm  2j1k  2ny4  2ny2  1wio  1qfo  1ugn  1j88  3h8n  2dli  1nko  1od7  1wwc  1mq8  2yr3  2nms  1im9  2ywz  1fcg  2otp  1qa9  1cdc  1f6a  2f8v  1rpq  3lqa  1cdj  2nzi  1ccz  3ay4  1fo0  2xac  1cdi  1zox  2c5d  1p7q  1e4k  1bqs  1x44  1nez  1p6a  1i8l  1wip  1qty  2cry  3rnq  1url  2bk8  1nam  1ncu  3bfo  1d3l  1ci5  1nct  3d5o  2w9l  1ovz  2j12  3moq  1ow0  2a38  1vdg  2ny6  1cdy  1o7s  2wbw  3o2d  1u9k  1gc1  1qsv  2om5  1jl4  1koa  3sgk  2dav  1eaj  1o7v  1rzj  1b6u  1ver  2ny0  3b5h  2fcb  2q87  2ec8  1tit  2cqv  1fnl  2ill  2j8h  1vsc  2ny3  2ol3  1cs6  1hng  1bih  2c9a  1oll  3dmm  1dqt  1itb  3ol2  1cdu  2i26  2e9w  1q8m  2coq  1g1c  1wit  1g0y  1t6v  1qsz  2dl2  2gk2  2g5r  1pd6  1gsm  3sbw  3bp5  1npu  2aw2  2i27  3k0w  1a64  1p69  1f5w  2bve  1ves  1sq2  1p6f  1hkf  1iam  3rnk  2z8v  1a6p  1kj2  1ic1  1xau  3cd4  1j89  1flt  2b4c  1wwa  2ny5  2i24  1efx  1kac  1a7b  1he7  1qfp  3sgj  1kb5  2df3  1m4k  1rsf  1t6w  1dr9  1g9n  2rq8  1uct  2qad  1www  2dks  2i25  2ifg  1rhf  1tiu  2j8o  2dyp  1h9v  2hrl  3jz7  2gw5  2vsd  1rv6  1g0x  2z8w  1p53  1j87  1ira  2ny1  2nxy  2nxz  3bik  1bd2  1oda  3bp6  1ufu  2oz4  3b9k  1rzk  1wiu  1nkr  2atp  1bqh  1g9m  1f2q  1vca  1tnn  1wiq  1od9  3d2u  1gxe  2avg  1olz  1mi5  1xed  2gi7  1smo  1t83  1e4j  1cdh  1cid  1ij9  2ywy  1ya5  1bpv  1waa  3mj7  1j86  3jwo  3jwd  1t89  2y7q  (a) Identify the active site residues for your chosen PDB entry. Active sites are indicated in the diagram below b) Images of the structure that illustrates the major structural features within the complex HCV NS3 protease domain–inhibitor complex structure (c) Identify those interactions which exist between the inhibitor and the enzyme. Illustrate with appropriate images how the inhibitor binds close to the enzyme active site. The diagram below shows the equilibrium between the enzyme and the inhibitor, which is further described by Equation 9.53 where the KI term represents dissociation constant: The scheme inhibition Mixed inhibition There are inhibitors that can bind both to the free enzyme as well as to the ES complex. These inhibitors represent a combination of the two already discussed types. The scheme of mixed inhibition is illustrated in Figure 9.10. Figure 9.10. Mixed inhibition In various cases of mixed inhibitions, the inhibitor binds to the ES complex and free enzyme. However, the case where KI is equal to KI` is also included The kinetic Equation 9.61 of mixed inhibition is also a grouping of all other previous equations: (d) Discuss how molecular modelling studies could be carried out to design improved inhibitors for the NS3 protease domain of HCV Structure of NS3 HCV Molecular modeling studies are vital in the designing of improved protein inhibitors for the NS3 domain of HCV. It is practical with various ways and mechanisms, which include simulations, molecular mechanics calculations and solvation. The diagram named “structure of NS3 HCV” shows the inhibitors in NS3, and is various parts. Simulations of inhibitor models of serine NS3 protease and their complexes carried using charge parameters and consistent force. Use a dielectric constant of 4 to experiment with all mechanics of molecules. The molecular mechanics calculations can then be used to take into account the protein shielding. Minimizations of the enzyme inhibitor complexes, free enzymes and free inhibitors are carried out by making sure that the structures are gradually relaxed. It can start with the side chains then the relaxation of the peptide backbone. Modelling studies can also be important when it comes to solvation. This is where the inclusion of solvent effects in the prediction (theoretical) of inhibition constants leads to an improved predictability of inhibitors of enzymes. Modeling through solvation has previously shown that solvent effects of species with ionic nature closely relates to Molecular charge. Q2. You are told by a colleague that a new web-site has appeared which predicts targets for microRNAs, URL www.targetscan.org. You are asked your opinion of the website. The website is so simple and sophisticated. It can only be used well and easily with somebody who has a biology background. It explains every step of the UTRs of genes of different types of animals or rather mammals. The website does offer an alternative room for navigation in case the first option is difficult for the student or the individual seeking information. For instance, there is information found on the website as a guide to a bioinformatician. It says that the 3 UTRs of many genes not fully annotated in humans than in mice. It goes ahead to explain that predictions of mice need to be obtained from the navigation space for TargetscanHuman, which may still be relevant in predicting mouse targets using mice arthologs of annotations from humans. The targetscan website gives a prediction of miRNA’s biological targets by looking for the availability of 7mer and 8mer sites that match the region of the seed of each miRNA. Nonconserved sites come out as predictions also, from the search. The site identifies sites that have mismatches in the seed region compensated by 3 pairing that is conserved. a) Decide on three criteria to assess the website and write a brief summary of the usefulness of the website to bioinformaticians, based on those three criteria. Targetscan website is viable when assessed through a number of criteria. In this case, I have chosen on three different criteria to use in making an assessment of this website. They include; Content of the website Ease in navigation References The website has diversified content in relation to information on biology, and molecular biology to be specific. It is a vital tool when it comes to bioinformatics seeking information in their field of study. Secondly, the website has ease in navigation because of the organization it has and the navigation tools that are easy to define and use appropriately. Lastly, the website has a section of references that guide the student or interested party to carry out further research on a given topic in case the information they find on the website is not sufficient. This positive aspect makes it unique and perfect for bioinformaticians. b) Use the web-site to find the miRNA(s) predicted to interact with the mRNA of human transferrin receptor 1 and write a brief summary of your findings. The predicted miRNA is cellular iron. This is as a result of their transcription and as such primary miRNA known as the (pri-miRNA) are always cleaved right at the stem and following that the structure of hairpin which is portrayed by the II-type RNase protein in Drosha as well as DGCR8which is its cofactor. c) Retrieve the mRNA / cDNA sequence of human transferrin receptor (TfR) from the EMBL / ENA file X01060 and identify the IREs in the mRNA. You can use the paper “Chicken transferrin receptor gene: conservation 3 noncoding sequences and expression in erythroid cells” Nucleic Acids Research vol 17, p3763, 1989 posted on WebLearn to help you. Summarise your findings. Simulations of inhibitor models of serine NS3 protease and their complexes carried using charge parameters and consistent force. Use a dielectric constant of 4 to experiment with all mechanics of molecules. The molecular mechanics calculations can then be used to take into account the protein shielding. Minimizations of the enzyme inhibitor complexes, free enzymes and free inhibitors are carried out by making sure that the structures are gradually relaxed. It can start with the side chains then the relaxation of the peptide backbone. d) Using an RNA folding programme, plot the local folding of the 3 UTR of the human TfR in the following regions: i) The binding site of the miRNAs ii) The first two IREs iii) The region between the second and third IREs. As expected, it is clear that indeed (i) and (iii) are single-stranded and (ii) has significant secondary structure. ​ [Note: plots of local folding of RNA were discussed in the lecture on RNA Structure and Function, slides 60 and 62. It is recommended to use a sliding window of 20 bases and calculate folding energies every 5 to 10 bases.] Q3 The modeling has proven that indeed the sequence is conjoined and that the biological setup is naturally intact. In the event that any point of the sequence gets out of phase, there is the likelihood that model shall not hold and the structure shall fail. This takes the intrigues of the bio set up to develop and in turn to run through. The resulting Bibliography MEISTER, G. (2010). Rna Biology. Weinheim, Wiley. Read More