Significance of Knotted Structures for Function of Proteins and Nucleic Acids
Poster Session II
30 – POS
Board 2
A Relationship between Coevolutionary Information, Folding Landscapes and the
Thermodynamics of Natural Sequence Selection
Faruck Morcos
, Nicholas P. Schafer, Ryan R. Cheng, Jose N. Onuchic, Peter G. Wolynes.
Rice University, Houston, USA.
As a consequence of evolutionary sequence optimization, natural proteins are energetically more
stable in their native state than in the molten globule states, resulting in an energy stabilization
gap. Although the mechanisms behind evolutionary optimization are far from being resolved, it
is possible to quantify the extent at which sequences have been optimized by such evolutionary
mechanisms in a framework consistent with current theories of protein folding and experimental
observations.
Methods
: We compare the landscape statistics for a transferable energy function that is
successful in structure prediction known as Associative memory, Water mediated, Structure and
Energy Model (AWSEM) with direct residue-residue couplings obtained using Direct Coupling
Analysis (DCA) and inferred from sequence alignments of protein families to estimate the
effective temperature at which natural, foldable protein sequences have been selected in
sequence space, T
sel
. This temperature quantifies the importance of folding energetics to
molecular evolution.
Results
: We considered eight different families, with abundant number of sequences (> 4500),
known experimental structures, lengths from 60 to 286aa and distinct folds. For each family, we
estimated the selection temperature T
sel
and the glass transition temperature T
g
for the native
sequences using experimentally determined folding temperatures T
f
and the relationship between
AWSEM and DCA Hamiltonians. We then computed T
f
/T
g
ratios, which are a metric of
evolutionary folding optimization.
Conclusions
: The resulting estimates of T
f
/T
g
are consistent with previous estimates based on
setting up correspondences with lattice models and through comparisons with laboratory folding
kinetics. Consistent estimates for T
sel
and T
f
/T
g
are also obtained using an alternate scheme,
which relies on the comparison of residue coevolution with experimental stability changes upon
single site mutations. Our results provide new evidence for funneling and suggest new directions
for protein modeling and design.
- 79 -
