Abstract
To function, biomolecules require sufficient specificity of interaction as well as stability to live in the cell while still being able to move. Thermodynamic stability of only a limited number of specific structures is important so as to prevent promiscuous interactions. The individual interactions in proteins, therefore, have evolved collectively to give funneled minimally frustrated landscapes but some strategic parts of biomolecular sequences located at specific sites in the structure have been selected to be frustrated in order to allow both motion and interaction with partners. We describe a framework efficiently to quantify and localize biomolecular frustration at atomic resolution by examining the statistics of the energy changes that occur when the local environment of a site is changed. The location of patches of highly frustrated interactions correlates with key biological locations needed for physiological function. At atomic resolution, it becomes possible to extend frustration analysis to protein-ligand complexes. At this resolution one sees that drug specificity is correlated with there being a minimally frustrated binding pocket leading to a funneled binding landscape. Atomistic frustration analysis provides a route for screening for more specific compounds for drug discovery.
Highlights
To function, biomolecules require sufficient specificity of interaction as well as stability to live in the cell while still being able to move
Distinct states distinctions possible, biasing the larger side chains to take up with higher probability some conformations rather than others. Such subtlety is not perfect, ; at equilibrium roughly 10% of the time any of the side chains can take on alternate configurations, which adds to the complexity of the functional protein-energy landscape[8,9,10]
The present approach to atomic resolution frustration analysis simplifies an earlier frustration localization algorithm working at the full atomistic level, that we recently put forward, that was computationally inefficient[11]
Summary
Biomolecules require sufficient specificity of interaction as well as stability to live in the cell while still being able to move. The mechanistic complexity biomolecules display is enabled by the selection of only a fraction of the residues in such a way that their interactions will conflict with each other compromising the stability of any single structure thereby allowing specific movements. This “frustration” of specific local interactions leads to an organized diversity of alternative states for the large biomolecule as a whole (Fig. 1). Most of the lessons from coarse-grained frustration analysis[3] turn out to be recapitulated at this atomic level
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