Protein functional landscapes, dynamics , allostery : atortuous path towards a universal theoretical framework

Energy landscape theories have provided a common ground for understanding the protein folding problem, which once seemed to be overwhelmingly complicated. At thesame time, the native state was found to be an ensemble of interconverting states with frustration playing a more important role compared to the folding problem. The landscape ofthe folded protein – the native landscape – is glassier than the folding landscape ; hence, ageneral description analogous to the folding theories is difficult to achieve. On the other hand,the native basin phase volume is much smaller, allowing a protein to fully sample its nativeenergy landscape on the biological timescales. Current computational resources may also beused to perform this sampling for smaller proteins, to build a ‘ topographical map ’ of the nativelandscape that can be used for subsequent analysis. Several major approaches to representingthis topographical map are highlighted in this review, including the construction of kineticnetworks, hierarchical trees and free energy surfaces with subsequent structural and kineticanalyses. In this review, we extensively discuss the important question of choosing propercollective coordinates characterizing functional motions. In many cases, the substates on thenative energy landscape, which represent different functional states, can be used to obtainvariables that are well suited for building free energy surfaces and analyzing the protein’sfunctional dynamics. Normal mode analysis can provide such variables in cases wherefunctional motions are dictated by the molecule’s architecture. Principal component analysis isa more expensive way of inferring the essential variables from the protein’s motions, one thatrequires a long molecular dynamics simulation. Finally, the two popular models for theallosteric switching mechanism, ‘ preexisting equilibrium ’ and ‘ induced fit ’, are interpretedwithin the energy landscape paradigm as extreme points of a continuum of transitionmechanisms. Some experimental evidence illustrating each of these two models, as well asintermediate mechanisms, is presented and discussed