ECS 129: Structural Bioinformatics March 15, 2016

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Notes: ES 129: Structural Bioinformatics March 15, 2016 1) The final exam is open book, open notes.

1 Notes: ES 129: Structural Bioinformatics March 15, ) The final exam is open book, open notes. 2) The final is divided into 2 parts, and graded over 100 points (with 8 points extra credit) 3) You can answer directly on these sheets (preferred), or on loose paper. 4) Please write your name at least on the front page! 5) Please, check your work! If possible, show your work when multiple steps are involved. Part I (20 questions, each 3 points; total 60 points) (These questions are multiple choices; in each case, find the most plausible answer) 1) Two homologous genes: ) Would be expected to have very similar sequences in related organisms B) Would be expected to be more similar in distantly related organisms than in organisms that are closely related ) May have become similar to each other by random mutations D) annot be found on the same genome E) ll of these 2) In the dynamic programming matrix below, what is the score in the cell identified with an interrogation mark (?). ssume that the score for a perfect match is set to 10, the score of a mismatch is set to 0, and gap penalties are ignored T W Y T T ? ) 20 B) 10 ) 30 D) 40 E) 0 3) The figure below shows a non-standard nucleotide base pair; identify it (note that dx indicates a deoxyribonucleotide, as contained in a DN molecule, while rx refers to a ribonucleotide, as found in an RN molecule). ) dg-d B) rg-r ) dg-r D) rg-d E) r-dg 1

4) The figure below shows a small peptide of six amino acids; give its sequence: (hint: there is one charged amino acid at physiological ph from ph 5.5 to ph 8.

2 4) The figure below shows a small peptide of six amino acids; give its sequence: (hint: there is one charged amino acid at physiological ph from ph 5.5 to ph 8.0) ) HYWPEF B) HFWPEY ) HFWPQY D) HFWPEF E) HFWPEW 5) Given the DN sequence S= 5 -GTT-3, how does the dotplot between S and its complementary, cs, look like? 6) The figure below shows a small fragment of a protein. From this figure, is it possible to define which extremity is the N-terminal, and which extremity is the -terminal? ) Yes: 1 is Nter, 2 is ter B) No: there is not enough information ) Yes, 1 is ter and 2 is Nter D) No: Nter and ter are only defined for nucleic acids E) No: we would need to know the sequence of this protein fragment 7) The so-called Rosetta stone for predicting protein-protein interactions is: ) Gene fusion B) Gene co-expression ) Presence of the name of the two proteins concerned in the same scientific paper D) very old stone recently found in Gizeh, Egypt, next to the Sphinx, that describes the code for protein-protein interactions in three scripts: hieroglyphic, demotic and Greek E) free software with high success rate 2

3 8) Which combination of program / substitution matrix will most likely give you the best alignment between two sequences that are highly similar? ) BLST / Blosum45 B) Dynamic programming / Blosum45 ) BLST / Blosum90 D) Dynamic programming / Blosum90 E) BLST / Blosum10 9) How many possible alignments, with no internal gaps, can you form when you compare a sequence of length 4 with a sequence of length 8? (Note that an alignment must have at least one letter match between the 2 sequences) ) 4 B) 8 ) 9 D) 10 E) 11 10) Only one of these techniques directly studies the behavior of a molecule as a function of time: ) Molecule dynamics B) Monte arlo sampling techniques ) Molecular mechanics D) Energy minimization E) Simulated annealing techniques 11) We want to find the best alignment(s) between the DN sequences GTTT and GTG. The scoring scheme S is defined as follows: S(i,j) = 1 if i = j, and S(i,j) = 0 otherwise. There is a constant gap penalty of -1 (penalty for the first position counts; see table below). The score Sbest and the number N of optimal alignments are (show your final dynamic programming matrix and the best possible alignment (s) for full credit): G T T T G -1 0 T -1 G

To do this, you first generate the cdn corresponding to the original protein (with your own choice for the codons you use), then mutate this cdn to get the sequence corresponding

4 ) Sbest = 3, N = 2 B) Sbest = 3, N = 1 ) Sbest = 4, N = 1 D) Sbest = 3, N = 3 E) Sbest = 4; N = 3 12) protein sequence contains one SP residue. You want to create a new protein sequence, with this SP being replaced with a TYR. To do this, you first generate the cdn corresponding to the original protein (with your own choice for the codons you use), then mutate this cdn to get the sequence corresponding to the new protein. What is the minimum number of mutations needed? ) 1 B) 2 ) 3 D) 0 E) None of the above 13) The Ramachandran plot of the protein structure 1axc in the PDB databank is given on the right. Which of the model of protein structures given below is most likely the corresponding structure: ) B) ) D) 4

5 14) single stranded DN contains 15% denine, as many Guanines as ytosines, and 40% of purines. What is the amount (in percent) of Thymine: ) 25% B) 15% ) 35% D) 40% E) Not enough information available 15) The protein sequence alignment shown below has a total score of 28. Knowing that the score for an exact match is 5 and the score for a mismatch is -4, what is the score used for the (constant, i.e. independent of length) gap penalty: GTGGG-G-T G----GGT ) -1 B) -2 ) -3 D) -4 E) Undefined (any value would give the same total score) 16) Docking is the process of predicting the conformation of the complex formed by a receptor and a ligand. Which of these four statements about docking is most likely to be true? ) Rigid, bound docking is the most difficult situation for predicting the conformation of the complex B) We only need the conformation of the receptor to perform docking ) The lock-and-key concept relates to rigid docking D) Docking can be solved with a simple energy minimization. 17) Dynamic programming, popular for sequence alignment, can also be used for spell checking. ssuming that a match is worth 10, a mismatch is worth 5, and a gap costs -5, which of these four words is closest to the word graffe typed by a user? Write the score of the optimal alignment next to each word (gaps at the start or at the end do not count). ) gaff B) graft ) grail D) giraffe 18) Let us consider the Luria and Delbruck experiment. The distribution of the number of mutations that occur during the growth of parallel cultures has a Poisson distribution. If there are no mutants, there were no mutations, and so the mean number of mutations m that occurs during the growth of a culture can be calculated from p 0, the proportion of cultures with no mutants: m = log p 0 ( ). Let us consider a bacterium B that is sensitive to a bacteriophage T, unless it carries a mutation M. 50 cultures of the bacterium, each with approximately 3 10^7 bacteria, are 5

6 subjected to the bacteriophage; 40 of those cultures show no resistance, i.e. none of their bacteria carried the mutation. Estimate the mutation rate µ per bacterium B: ) ^(-9) B) ^6 ) D) 1 10^(-9) E) Not enough information available 19) You want to design a small peptide that can interact with the TT box of a specific gene (the TT box is a small DN sequence upstream from the gene that serves as transcription initiator). Your constraints are: the peptide should contain a strand (at least predicted to be mostly in extended conformation, based on hou and Fassman, see appendix D), and it should contain 12 residues. Which of the following peptide would be a good candidate? ) MPGLPQLGLP B) MPGLEWQLPGLP ) MLGYTWTTVSVT D) MVTTVWYVTGT 20) The cdn corresponding to a small peptide is TGTTGTTGGGGGTTT TG. The corresponding amino acid sequence is Met-Tyr-sp-Glu-ys--Gly-Pro-Leu-Stop. mutation occurs at the DN level, with the at position 15 being substituted with T. What effect do you think this mutation might have on the expression of this gene? ) It introduces a stop codon and the peptide will be shorter B) The ys in position 5 of the protein sequence will be replaced with Trp ) The Start and Stop codons won t be in phase anymore and the gene won t be expressed D) This is a silent mutation as it will have no impact on the protein sequence Part II (2 problems; total 48 points) 6

7 Problem 1 (4 questions, each 10 points) 1) The following eukaryotic DN sequence was given to you: 5 -TTGGTTGGGGGTTGGTGG-3 You are told that this sequence, or its complementary, codes for one gene. Find the longest gene, or open reading frame (ORF) corresponding to this DN sequence; remember that there are 6 possibilities, i.e. 3 possible reading frames for one strand and 3 possible reading frames for its complementary. Transcribe this ORF into an RN sequence 2) s this is a eukaryotic sequence, it may contain an intron. For simplicity, we will assume that introns always start with GU and end with. Identify all possible introns, and explain why their removal would result in the loss of the gene. 7

8 3) Based on question 2 just above, we know that the RN is not spliced. Find the sequence of the protein it encodes. 4) Predict the secondary structure of this protein using the hou and Fassman method, with the propensities given in ppendix D 8

9 Problem 2 (8 points) You have isolated an important gene that regulates the size of a newly found frog from the island of Borneo. You have also been able to find the sequence of the protein encoded by this gene. You suspect that sequences similar to this sequence can be found in other organism, but with circular permutation: Initial sequence N amino acids Permuted sequence In a circular permutation, N amino acids (N can take any value between 1 and M-1, where M is the total length of the protein) at the end of the original sequence will appear at the beginning of the permuted sequence (i.e. before the remaining M-N amino acids). Propose an efficient strategy for detecting all possible permuted sequences of your frog sequence in a large database of protein sequences. 9

10 10

11 ppendix : mino cids Hydrophobic mino cids GLY (G) D L () B G2 G B Val (V) G1 D2 B Leu (L) Z E1 G D1 G1 B Ile (I) G2 D N Pro (P) B E2 D2 G B D1 E Phe (F) B G S D Met (M) Polar mino cid (S) B OG Z2 NE E2 1 D1 G Trp (W) D2 B OG1 E3 B Thr (T) H Z3 G2 B OD1 G E2 D2 sn (N) G B Tyr (Y) ND2 OH Z E1 D1 B B Gln (Q) D2 NE 2 E1 His (H) OE1 G G D ND1 NE2 11

12 Polar mino cids NZ OE1 G D OE2 D E NH2 Z NH1 B B G NE B rg (R) D G Glu (E) SG B Lys (K) OD1 B G OD2 ys () sp (D) ppendix B: Nucleotides Uracyl (U) 12

13 ppendix : Genetic ode U G U G Phe Phe Leu Leu Leu Leu Leu Leu Ile Ile Ile Met/Start Val Val Val Val Pro Pro Pro Pro Thr Thr Thr Thr la la la la Tyr Tyr STOP STOP His His Gln Gln sn sn Lys Lys sp sp Glu Glu ys ys STOP Trp rg rg rg rg rg rg Gly Gly Gly Gly U G U G U G U G ppendix D: hou and Fassman Propensities mino cid Helix Strand Turn la ys Leu Met Glu Gln His Lys Val Ile Phe Tyr Trp Thr Gly sp sn Pro rg

7.014 Solution Set 4

7.014 Solution Set 4 Question 1 Shown below is a fragment of the sequence of a hypothetical bacterial gene. This gene encodes production of HWDWN, protein essential for metabolizing sugar yummose. The