Abstract
BackgroundLong-range communication is very common in proteins but the physical basis of this phenomenon remains unclear. In order to gain insight into this problem, we decided to explore whether long-range interactions exist in lattice models of proteins. Lattice models of proteins have proven to capture some of the basic properties of real proteins and, thus, can be used for elucidating general principles of protein stability and folding.ResultsUsing a computational version of double-mutant cycle analysis, we show that long-range interactions emerge in lattice models even though they are not an input feature of them. The coupling energy of both short- and long-range pairwise interactions is found to become more positive (destabilizing) in a linear fashion with increasing 'contact-frequency', an entropic term that corresponds to the fraction of states in the conformational ensemble of the sequence in which the pair of residues is in contact. A mathematical derivation of the linear dependence of the coupling energy on 'contact-frequency' is provided.ConclusionOur work shows how 'contact-frequency' should be taken into account in attempts to stabilize proteins by introducing (or stabilizing) contacts in the native state and/or through 'negative design' of non-native contacts.
Highlights
Long-range communication is very common in proteins but the physical basis of this phenomenon remains unclear
Evidence for such coupling initially emerged through studies of allosteric regulation of proteins [1] when it became clear that allosteric control is often achieved by ligand binding-induced conformational changes that are propagated from one ligand binding site to other distant sites
double-mutant cycle (DMC) were invoked in order to evaluate, for the first time to the best of our knowledge, coupling energies between all possible pairs of positions in 2D and 3D lattice models of proteins (Figure 1)
Summary
Long-range communication is very common in proteins but the physical basis of this phenomenon remains unclear. There is a wealth of information that indicates that distant sites in proteins are often coupled to each other energetically. It became possible to identify distant sites in proteins that are coupled to each other energetically by protein engineering through the use of the double-mutant cycle (DMC) method [for review see ref. One class of computational methods is based on detection of co-evolving residues in multiple sequence alignment data. Such methods were originally developed (page number not for citation purposes)
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