Designing pH induced fold switch in proteins

Abstract

This work investigates the computational design of a pH induced protein fold switch based on a self-consistent mean-field approach by identifying the ensemble averaged characteristics of sequences that encode a fold switch. The primary challenge to balance the alternative sets of interactions present in both target structures is overcome by simultaneously optimizing two foldability criteria corresponding to two target structures. The change in pH is modeled by altering the residual charge on the amino acids. The energy landscape of the fold switch protein is found to be double funneled. The fold switch sequences stabilize the interactions of the sites with similar relative surface accessibility in both target structures. Fold switch sequences have low sequence complexity and hence lower sequence entropy. The pH induced fold switch is mediated by attractive electrostatic interactions rather than hydrophobic-hydrophobic contacts. This study may provide valuable insights to the design of fold switch proteins.

A study on the secondary structure of the metalloregulatory protein CueR: effect of pH, metal ions and DNA

“…Studies on these effects may led to the design of proteins that possess pH-dependent folds interconverted into each other by the change of pH (Baruah and Biswas 2015;Boyken et al 2019). For these reasons, the development of pKa estimation methods based on molecular dynamics simulations proved to be indispensable (Cabra et al 2006;Hansson et al 2002;Langella et al 2004;Mishra et al 2015;Oliveira et al 2016;Perilla et al 2015).…”

Criticality in the conformational phase transition among self-similar groups in intrinsically disordered proteins: Probed by salt-bridge dynamics

“…In contrast, there are multi-functional proteins as well, wherein, different parts of the protein 3D structure (e.g., domains, active and allosteric sites) serve to implement the few functions they are evolved to deliver. While, these molecular evolutionary strategies serve to construct the general rules of the protein structure-function paradigm, another variant has recently been discovered in the protein world, namely, fold-switch proteins [10] which switch between (a few) folds to support more than one functionality, generally induced by their chemical environment [11]. However, in all these cases, the notion of multi-functionality only varies within a few types of (premeditated) functions structurally not allowing the scope to get involved in sudden emergency ad-hoc functionalities as may be required contextually.…”

In silico design of misfolding resistant proteins: the role of structural similarity of a competing conformational ensemble in the optimization of frustration

“…An energy based foldability criterion quantifies the compatibility of a sequence with a given structure in terms of an optimized energy function. 51–53 Positive design and negative design are the two approaches used for protein sequence design. The positive design approach is based on stabilization of the target conformation using a suitable energy function.…”