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Engineering | Undergraduate Research

Predicting the impact of point mutation on Protein Structure

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Dr. Zoe Lacroix, Associate Research Professor in the Polytechnic School, is seeking a future FURI applicant or Honors Research/Thesis student to work on the “Predicting the impact of point mutation on Protein Structure” project.

Amino acid substitution is now considered as a major constraint on protein evolvability, while it was previously admitted that most positions can tolerate drastic sequence changes, provided the fold is conserved (see review by Tokuriki and Stawfik, 2009). Actually, mutations affect stability and stability affects evolution. The level of deleterious mutations can be as high as one third. Therefore, the prediction of the effects of residue substitution can be of great help in wet labs. Due to evolution, the number of stabilizing mutations is smaller than for destabilizing ones. One must mention that a stabilizing mutation is not necessarily related to an improved efficiency of the mutated protein, as far as function is concerned. Sometimes, a more stable structure results in an increased rigidity, while the function requires a certain level of flexibility. This is the case, for instance, with the enzyme catalysis (Worth et al., 2011). Therefore, it seems reasonable to place a threshold of 2 kcal/mol in either ways of ∆∆G (stabilizing or destabilizing) in order to claim a putative malfunction. Mutations in conserved positions usually cause large stability decreases.

In this project, we aim at improving our current consensus method taking an average of various stability analyses to predict the impact of point mutation on protein structure (see SPROUTS at and Lonquety et al., 2009). The current method focuses only on the thermodynamic contribution to stability, which can be considered as acceptable for small and medium size proteins (500 AA maximum length). We wish to explore how other methods such as the prediction of Most Interacting Residues (MIR) can improve the prediction on the impact of mutation.

Dr. Lacroix is inviting talented undergraduate students to join her team to contribute to the project and help revising and extending the method to predict the impact of point mutation on protein structure. Students interested to join the team will work closely with a graduate student and under the supervision of Dr. Lacroix. Successful undergraduate students typically have the opportunity to co-author research papers and present their work at workshops and conferences.

This is an opportunity that is eligible for the FURI program. Barrett Honors College students are also welcome to apply to work on their honors research/thesis.

Students should apply by sending their resume, cover letter, and unofficial transcripts to Dr. Lacroix at

Tokuriki, N., and Tawfik, D. S. (2009) Stability effects of mutations and protein evolvability. Curr. Opin. Struct. Biol., 19(5), 596-604.
Worth, C. L. , Preissner, R. , and Blundell, T. L. (2011) SDM–a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Res., Jul;39(Web Server issue), W215-222.
Lonquety, M., Lacroix, Z., Papandreou, Z., and Chomilier, J. (2009) SPROUTS: a database for the evaluation of protein stability upon point mutation.  Nucleic Acids Res., 37, D374–D379. doi: 10.1093/nar/gkn704.
Acuña, R., Lacroix, Z., Papandreou, Z., and Chomilier, J. (2014)SMIR: a method to predict the residues involved in the core of a protein. BIOCOMP 2014 – to be published.


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