XLIII Annual Meeting of SBBq
th
th
Foz do Iguaçu, PR, Brazil, May 17 to 20 , 2014
Visualization of Protein Folding Funnels in Structure-based Models
Oliveira Junior, A. B.; Leite, V. B. P.
Departamento de Física, IBILCE, UNESP, São José do Rio Preto, SP, Brazil
Introduction: Protein folding occurs in a very high dimensional phase space, whose
exponentially large number of states, represented in terms of one effective reaction
coordinate, exhibit a topology resembling a funnel, according to the energy
landscape theory. Since the role of each local minimum is not considered in this
statistical approach, the folding mechanism is unveiled by describing the local
minima in an effective one-dimensional representation. Objectives: Apply a metric to
describe the distance between any two conformations, which allows to go beyond the
one-dimensional representation and visualizing the folding funnel in 2D and 3D.
Material and Methods: Computer simulation of protein folding were performed using
structure-based model, particularly the C-alpha approximation. Two distinct proteins
were studied, CI2 and SH3 (from the 1YPA and 1SHG pdb, respectively). The
projection of these multidimensional data was performed using a metric based on the
ratio between conformational similarity (Jaccard index) and dissimilarity (Jaccard
distance). Results and Discussion: The visualization allows assessing the folding
process in detail, e.g. by identifying the connectivity between conformations and
establishing the paths that lead to the native state. Distinct funnels were generated
according to the native state structure. The analysis was restricted to conformations
from the transition-state to the native configuration. Due to the large number of
structures, the visualization was divided into regions of energy, allowing better
description of the states close to the native state. Conclusion: Consistent with the
expected results from the energy landscape theory, folding routes can be visualized
to probe different regions of the phase space, as well as to characterize metastable
states. This methodology can be applied to infer the conformational effects of small
mutations.
Keywords: energy landscape theory, multidimensional reduction, protein comparison
metric
Acknowledgments: CAPES, FAPESP, CNPq