Analysing the origin of long-range interactions in proteins using lattice models

Background: Long-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. Results: Using 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. Conclusion: Our 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.