Abstract
The high-resolution refinement of docked protein-protein complexes can provide valuable structural and mechanistic insight into protein complex formation complementing experiment. Monte Carlo (MC) based approaches are frequently applied to sample putative interaction geometries of proteins including also possible conformational changes of the binding partners. In order to explore efficiency improvements of the MC sampling, several enhanced sampling techniques, including temperature or Hamiltonian replica exchange and well-tempered ensemble approaches, have been combined with the MC method and were evaluated on 20 protein complexes using unbound partner structures. The well-tempered ensemble method combined with a 2-dimensional temperature and Hamiltonian replica exchange scheme (WTE-H-REMC) was identified as the most efficient search strategy. Comparison with prolonged MC searches indicates that the WTE-H-REMC approach requires approximately 5 times fewer MC steps to identify near native docking geometries compared to conventional MC searches.
Highlights
Protein-protein interactions are integral to many mechanisms of cellular activities, ranging from enzyme catalysis and inhibition to signal transduction and gene regulation
The well-tempered ensemble method combined with a 2-dimensional temperature and Hamiltonian replica exchange scheme (WTE-H-Replica Exchange Monte Carlo (REMC)) was identified as the most efficient search strategy
Comparison with prolonged Monte Carlo (MC) searches indicates that the WTE-H-REMC approach requires approximately 5 times fewer MC steps to identify near native docking geometries compared to conventional MC searches
Summary
Protein-protein interactions are integral to many mechanisms of cellular activities, ranging from enzyme catalysis and inhibition to signal transduction and gene regulation. Atomic-level structural knowledge is essential to understand the function of protein-protein complexes in biological processes. Computational protein-protein docking methods can provide structural models of protein-protein interactions where experimental data is absent, of low-resolution or too sparse. Besides providing valuable structural biology information, high-resolution protein-protein docking can help to explain binding affinities and specificities, the nature of the binding free energy funnel and effects of mutations. These techniques are essential for computational protein-protein interface design of the design of non-natural complexes [3,4,5,6,7]
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