Evolved Minimal Frustration in Multifunctional Biomolecules

Abstract

Protein folding is often viewed in terms of a funneled potential or free energy landscape. A variety of experiments now indicate the existence of multifunnel landscapes, associated with multifunctional biomolecules. Here, we present evidence that these systems have evolved to exhibit the minimal number of funnels required to fulfill their cellular functions, suggesting an extension to the principle of minimum frustration. We find that minimal disruptive mutations result in additional funnels, and the associated structural ensembles become more diverse. The same trends are observed in an atomic cluster. These observations suggest guidelines for rational design of engineered multifunctional biomolecules.

Is the H4 histone tail intrinsically disordered or intrinsically multifunctional?

“…While these roles cannot be assigned from the current calculations, the relationship between multiple funnels and multiple functions is established for other systems. 81 The existence of a well-defined set of funnels supporting distinct structures is qualitatively different from the disorder characterised for structural glasses. 107,108 The distinct ensembles may facilitate the formation of different bound complexes, helping to provide the necessary transience required for the liquid-like chromatin organisation.…”

“…The existence of multiple, stable funnels gives this system a multifunnel character. Such character has been associated with multifunctionality before, 81 and hints at an evolved minimisation of frustration in the system. [82][83][84][85] Indeed, when comparing the frustration index 86 for the histone tail with the one derived form the potential energy landscape for Aβ monomers, 41 we observe an order of magnitude lower frustration at low temperatures for the histone tail (see supporting information).…”

“…Instead, the different structures present different options for binding to other molecules, and we suggest that this organisation may correspond to evolved multifunctionality. 81,85 The apparent stability and robustness of the energy landscape would facilitate chromatin binding. Recently, work on the H1 N-terminal domain revealed that while the region is disordered in solution, a disorderto-order transition increases its binding affinity.…”

“…This relation between multiple funnels observed and intrinsic multifunctionality consistent with the notion of evolved minimal frustration for biomolecules. 81 To achieve the liquid-like organisation of chromatin 37,91 transient binding of the histone tails is necessary. Recent work 92,93 showed that intrinsic liquid-liquid phase separation is a key factor in chromatin organisation.…”

Energy Landscapes for Proteins: From Single Funnels to Multifunctional Systems

“…Another consequence of point mutations is increased frustration, which correlates with greater structural variation. [19] As a consequence, alterations of naturally occurring sequences to obtain new functionality, as well as de novo sequence designs, will most likely exhibit frustrated landscapes, leading to a number of competing structural ensembles and functions. The design process should therefore aim to reduce the frustration, while at the same time improving the functionality.…”