Annual Scientific Report 2015

Thornton Group
Proteins: Structure,
Function and Evolution
The goal of our research is to understand how biology works at the molecular
level, with a particular focus on protein structure and evolution and ageing.
We explore how enzymes perform catalysis by gathering
relevant data from the literature and developing novel
software tools that allow us to characterise enzyme
mechanisms and navigate the catalytic and substrate
space. In parallel, we investigate the evolution of
these enzymes to discover how they can evolve new
mechanisms and specificities. This involves integrating
heterogeneous data with phylogenetic relationships
within protein families, which are based on proteinstructure
classification data derived by colleagues at
University College London (UCL). The practical goal
of this research is to improve the prediction of function
from sequence and structure and to enable the design of
new proteins or small molecules with novel functions.
We also explore sequence variation between individuals,
especially those variants related to diseases.
To understand more about the molecular basis of
ageing in different organisms, we participate in a close
collaboration with experimental biologists at UCL. Our
role is to analyse functional genomics data from flies,
worms and mice and, by developing new software tools,
relate these observations to effects on lifespan.
Major achievements
Chemistry and evolution of isomerases
Biologists are challenged with the functional
interpretation of vast amounts of sequencing data
derived from genomics initiatives. Among all known
proteins, the function of enzymes is probably the most
investigated and best described at the molecular level.
Together with enzymes changing the redox state of
substrates and transferring chemical groups between
molecules, isomerases catalyse interconversion
of isomers, molecules sharing the same atomic
composition but different arrangements of chemical
groups. In this study (Martinez-Cuesta et al, 2016),
we catalogued the isomerisation reactions known to
occur in biology using a combination of manual and
computational approaches. This method provides
a robust basis for comparison and clustering of the
reactions into classes. Comparing our results with the
Enzyme Commission (EC) classification, the standard
approach to represent enzyme function on the basis of
the overall chemistry of the catalysed reaction, expands
our understanding of the biochemistry of isomerization.
The grouping of reactions involving stereoisomerism
is straightforward with two distinct types (racemases/
epimerases and cis-trans isomerases), but reactions
entailing structural isomerism are diverse and
challenging to classify using a hierarchical approach.
This study provided an overview of which isomerases
occur in nature, how we should describe and classify
them, and their diversity.
Large-scale analysis exploring evolution
of catalytic machineries and mechanisms
in enzyme superfamilies
Enzymes, as biological catalysts, form the basis of all
forms of life, but how these proteins have evolved their
functions remains a fundamental question in biology.
Using a range of computational tools and resources we
compiled information on all experimentally annotated
changes in enzyme function within 379 structurally
defined protein domain superfamilies, linking the
changes observed in functions during evolution, to
changes in reaction chemistry (Furnham et al, 2015).
Many superfamilies show changes in function at
some level, although one function often dominates
one superfamily. We used quantitative measures of
changes in reaction chemistry to reveal the various
types of chemical changes occurring during evolution
and provided detailed examples. We used structural
information of the enzymes’ active sites to examine how
different superfamilies have changed their catalytic
machinery during evolution. Some superfamilies
have changed the reactions they perform without
changing catalytic machinery; in others, large changes
of enzyme function, both in terms of overall chemistry
and substrate specificity, have been brought about by
significant changes in catalytic machinery. Interestingly,
the relatives of some superfamilies perform similar
functions using different catalytic machineries. Our
analysis highlighted characteristics of functional
evolution across a wide range of superfamilies, providing
insights that are useful in predicting the function of
uncharacterised sequences and in the design of new
synthetic enzymes.
Longevity GWAS using the Drosophila
Genetic Reference Panel
The results of our genome-wide association study
(GWAS) for Drosophila lifespan, based on 197
Drosophila Genetic Reference Panel (DGRP) lines
(Ivanov et al. 2015), suggested that the top associated
genes provide good candidates for further
investigation into their relationship
with lifespan and ageing. While our
147
2015 EMBL-EBI Annual Scientific Report