Molecular Mechanisms of Protein Evolution
How has the repertoire of remarkably diverse protein functions evolved in nature? We are interested in understanding the evolutionary dynamics of biological molecules and systems and, in particular, how evolution has generated the diverse array of genes (proteins and enzymes) that cohesively work together to function as complex cells and organisms. Current knowledge of the molecular mechanisms of protein evolution is limited: What drives the generation of a new protein function? How many mutations are required to change one enzyme to another? Is the order of mutations important for the course of evolution? What makes a sequence (gene) particularly “evolvable” for the generation of new functions? We aim to understand the molecular basis of evolution, i.e., how a mutation causes structural and biophysical changes to a protein, and eventually leads to functional changes. Understanding the molecular mechanisms of evolution addresses, not only 3 billion years of evolutionary history on earth, but also on-going evolution of extant proteins (e.g., drug resistance, and the degradation of xenobiotic compounds).
Our scientific approach is interdisciplinary, we employ a wide variety of research techniques, including laboratory evolution and protein engineering techniques, molecular and structural biology, protein biochemistry and biophysics, and bioinformatics. We extensively employ an “experimental evolution” approach, a technique that is used to mimic evolutionary processes in the laboratory, and to reconstruct the evolutionary trajectories of biological molecules. In doing so, we study the molecular mechanisms of protein evolution that underlie the diverse range of functions that are observed in modern enzymes. Furthermore, we utilize and apply the knowledge gained from evolutionary biochemistry to generate and engineer novel proteins, metabolic pathways and organisms.
Please visit our homepage (http://tokurikilab.msl.ubc.ca) to see more about our research program.
We are looking for graduate students to start in the fall of 2018. Please email me if you are interested in applying.
Clifton BF, Kaczmarski JA, Carr PD, Gerth ML, Tokuriki N, Jackson CJ “Evolution of an enzyme from a solute-binding protein”, submitted
Akiva E†, Copp JN†, Tokuriki N*, Babbitt PC* “Evolutionary and molecular foundations of multiple contemporary functions of the nitroreductase superfamily” submitted.
Baier F, Copp JN, Tokuriki N* “Evolution of enzyme superfamilies: comprehensive exploration of sequence-function relationships” Biochemistry, 2016, 55 (46), 6375-6388
Kaltenbach M, Emond S, Hollfelder F & Tokuriki N* “Functional trade-offs in promiscuous enzymes cannot be explained by intrinsic mutational robustness of the native activity” PLoS Genet, 2016, 12 (10): e1006305
Yang G†, Hong N†, Baier F, Jackson CJ*. & Tokuriki N* “Conformational tinkering through indirect effects of mutations drives evolution of a promiscuous activity” Biochemistry, 2016, 55 (32): 4583-4593
Purg M, Pabis A, Baier F, Tokuriki N, Jackson C & Kamerlin SCL, “Probing the mechanisms for the selectivity and promiscuity of methyl parathion hydrolase” Philosophical Transactions A, 2016, 374 (2080)
Campbell E†, Kaltenbach M†, Carr P, Livingstone E, Jurnou L, Weik M, Tokuriki N* & Jackson CJ*, “The role of protein dynamics in the evolution of new enzyme function” Nature Chem Biol, 2016, 12(11): 944-950.
Miton CM & Tokuriki N* “How mutational epistasis impairs predictability in protein evolution and design” Protein Sci, 2016, 25 (7): 1260-72 (This paper is selected as 2017 Best Paper in Protein Science!)
Kaltenbach M, Campbell E, Hyvonen M, Jackson CJ, Hollfelder F, & Tokuriki N* “Reverse evolution leads to an efficient enzyme incompatible with its ancestor” eLife, 2015, 10.7554/eLife.06492.
Baier F, Chen J, Solomonson M, Strynadka N, & Tokuriki N* “Distinct metal isoforms underlie promiscuous activity profiles of metalloenzymes” ACS Chem Biol, 2015 10 (7): 1684-93
Kaltenbach M &Tokuriki N* “Generation of effective libraries by neutral drift” Methods Mol Biol, 2014, 1179: 69-81
Tokuriki N & Jackson CJ “Enzyme dynamics and engineering: one step at a time” Chem Biol, 2014, 21(10): 1259-60
Emond S, Socha RS, Tokuriki N* “Strategies to overcome stability constraints in enzyme evolution and facilitate effective enzyme engineering” Industrial Biocatalysis (Pan Stanford), 2014, 115-160
Baier F & Tokuriki N* “Connectivity between the catalytic landscapes of various members of the metallo-β-lactamase superfamily” J Mol Biol, 2014, 426(13): 2442-56
Kaltenbach M & Touriki N* “Dynamics and constraints of enzyme evolution” J Exp Zool B Mol Dev Evol, 2014, 322(7): 468-87
Wygnowski KT†, Kaltenbach M†, Tokuriki N* “GroEL/ES buffering and compensatory mutations promote protein evolution by stabilizing folding intermediates.”J Mol Biol, 2013, 425(18): 3403-14
Socha RD, Tokuriki N* “Modulating protein stability: Directed evolution strategies for improved protein function.” FEBS Journal, 2013, 280: 5582-5595
Tokuriki N*, Jackson CJ, Afriat-Jurnou L, Wygnowski KT, Tang R & Tawfik DS* “Diminishing returns and tradeoffs constrain the evolutionary optimization of an enzyme” Nature Comm, 2012 3: 1257
Tokuriki N & Tawfik DS “Stability effect of mutations and protein evolvability” Curr Opin Struct Biol, 2009, 5: 596-604
Tokuriki N & Tawfik DS “Chaperonin overexpression promote genetic variation and enzyme evolution” Nature, 2009, 459: 668-673
Tokuriki N & Tawfik DS “Protein dynamism and evolvability” Science, 2009, 324: 203-207
Please see the full list of our publications, http://tokurikilab.msl.ubc.ca/publications/