Practical 6

Some final questions

Aims

• To give an opportunity for reflection on some themes from the course.

Objectives

After this practical you will be able to:

• identify situations where methods can be applied across different application areas;
• critically discuss problems and methods in computational bioinformatics.

Exercise

1. Give three examples of the application simulated annealing: two in bioinformatics and one example in another area (not related to bioinformatics). For each example, briefly describe (i) how solutions are generated and (ii) how solutions are scored.

2. On page 219 of the article by Simons et al. (1997) the authors state: "the similarity in topology is clear ... in the contact map (Figure 9B)". Explain what the authors mean by this.

3. On page 972 of the article by Morris et al. (2002) the authors state: "The presence of cis-peptides adds an extra complication that we have chosen to ignore". Discuss this "complication", and why the authors chose to ignore it.

4. Discuss how the concept of mesostates (as described by Gong et al. (2005), or Chellapa and Rose (2012)) could be used in performing structural alignment.

   Briefy discuss any advantages or disadvantages of this approach to structural alignment, compared with one published method for structural alignment (e.g. one of those listed under topic 1 in Practical 4).

5. Protein Data Bank entry 1QYS contains an crystal structure of the computationally designed protein Top7 (Kuhlman et al., 2003). Suggest 2 amino acid residue mutations that, for different reasons, might reduce the stability of Top7, or even prevent it from adopting a stable fold. Suggest another mutation that would be unlikely to affect the protein's stable fold. Give reasons to justify your choices.

References

• Chellapa, G.D. and Rose, G.D. (2012) Reducing the dimensionality of the protein-folding search problem. Protein Science, 21, 1231-1240 (doi:10.1002/pro.2106)
• Gong, H., Fleming, P.J. and Rose, G.D. (2005) Building native protein conformation from highly approximate backbone torsion angles. Proc. Natl. Acad. Sci. U.S.A., 102, 16227-16232 (doi:10.1073/pnas.0508415102)
• Kuhlman, B., Dantas, G., Ireton, G.C., Varani, G., Stoddard, B.L. and Baker, D. (2003) Design of a novel globular protein fold with atomic-level accuracy. Science, 302, 1364-1368 (doi:10.1126/science.1089427)
• R. J. Morris, A. Perrakis and V. S. Lamzin (2002) ARP/wARP's model-building algorithms. I. The main chain. Acta Cryst., D58, 968-974. (doi:10.1107/S0907444902005462)
• Simons, K.T., Kooperberg, C., Huang, E. and Baker, D. (1997) Assembly of Protein Tertiary Structures from Fragments with Similar Local Sequences using Simulated Annealing and Bayesian Scoring Functions. J. Mol. Biol., 268, 209-225 (doi:10.1006/jmbi.1997.0959)

What to submit

You should submit your solutions as PDF or plain text via the Fire system before 23:59 on Wednesday 11 January 2017.

Everyone should do question 1. Those aiming for a higher grade should also attempt the other questions.