Role of conformational heterogeneity on protein misfolding

Abstract

Conformational fluctuations in the native state ensemble play an important role in designing protein sequences that fold into a particular native structure. In this work, the results of a self-consistent field theory are applied to investigate the role of ‘misfold fluctuations’ in the native state ensemble by optimizing the generalized foldability criterion. The conformational heterogeneity is measured by the similarity in the structural context of the residues while the sequence–structure compatibility is evaluated in terms of a simple coarse grained energy function. Sequences designed for a similar foldability range may adopt folded, unfolded or misfolded conformations by tuning the degree of conformational heterogeneity in the native state ensemble. With the increase in the fluctuations of the native state ensemble, the protein gains structural flexibility at the expense of stability and the minimum energy conformation is different, but structurally similar to that of the native/target one. The conformational fluctuations in the native state ensemble also change the overall surface accessibility of some specific core/surface sites which may give rise to some unfavorable interactions with the environment consequently leading to misfolding. The theory is valid for both lattice and real proteins indicating a promising route to evaluate design algorithms where some sequences may fold to structures other than the chosen native/target conformation.