Abstract
Most of the current docking procedures are focused on fine conformational adjustments of assembled complexes and fail to reproduce large-scale protein motion. In this paper, we test a new modeling approach developed to address this problem. CABS-dock is a versatile and efficient tool for modeling the structure, dynamics and interactions of protein complexes. The docking protocol employs a coarse-grained representation of proteins, a simplified model of interactions and advanced protocols for conformational sampling. CABS-dock is one of the very few tools that allow unrestrained docking with large conformational freedom of the receptor. In an example application we modeled the process of complex assembly between two proteins: Troponin C (TnC) and the N-terminal helix of Troponin I (TnI N-helix), which occurs in vivo during muscle contraction. Docking simulations illustrated how the TnC molecule undergoes significant conformational transition on complex formation, a phenomenon that can be modeled only when protein flexibility is properly accounted for. This way our procedure opens up a new possibility for studying mechanisms of protein complex assembly, which may be a supporting tool for rational drug design.
Highlights
The development of new drugs is one of the most challenging tasks in science today
Computational modeling and simulations have become integral procedures in introducing new drugs to the market and it is safe to assume that the role of theoretical computations in this field will increase in the future [1]
During the Replica Exchange Monte Carlo (REMC) coarse-grained simulation we obtained a large cluster of near-native conformations in the lowest temperature replica (T = 1.5)
Summary
The development of new drugs is one of the most challenging tasks in science today. Combined efforts of the pharmaceutical industry, academic researchers and biotech companies have improved the process of drug design, and contributed to advances in science itself. Protein activity in organisms involves interactions with other biomolecules, which makes them perfect targets for rationally designed drugs. What is needed, is a complete description of the structure and dynamics of the protein along with its interacting partners. Such a demand from the pharmaceutical industry has recently forced transition in the development of theoretical methods for protein examination: from protein structure prediction to the modeling of whole protein complexes. The emphasis in protein modeling is nowadays being put more on obtaining a dynamic picture of a protein system than a simple static structure
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