Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Exploring the Role of Protein-Protein Interactions in the Mechanical Unfolding of Protein Assemblies
Dynamic force spectroscopy methods provide unique opportunities for directly probing the free energy landscape of complex biomolecules. However, even if they provide information on the chain extension of the molecule, they cannot supply full details of the populated structures. This is especially true in the case of multi-domain or multi-chain proteins for which the complexity of the fold translates into many unfolding scenarios. An assumption employed by the majority of experiments for the interpretation of the force-unfolding of such proteins is that the behavior of the ensemble is the sum of its parts. While this assumption is likely to apply to tandems of identical units, for hetero-protein tandems or whenever units are connected by interfaces as in multi-domain or multi-chain complexes this assumption needs to be revisited.
I will present our investigations into the role of protein-protein interactions through simulations of the biomechanical unfolding reactions of multi-domain and multi-chain protein complexes covering a range of fundamental cellular functions from fusion to cytoskeletal support in real (experimental) time (1,2). To obtain the force extension curves using experimental pulling speeds, we employed a coarse-grained minimalist model (SOP model) (3) of proteins to carry out overdamped Langevin simulations implemented on Graphics Processing Units (GPUs). GPUs have unleashed tremendous computational power that has been utilized in a wide range of scientific applications. The system size dependent 10-90-fold computational speedup on a GPU, compared to an optimized CPU program, enabled us to follow the dynamics in the centisecond timescale (4). While our model reproduces the experiments, we find that the independence assumption needs to be critically assessed. I will discuss the signature of the protein-protein interactions as a function of the applied vector force, and the connection between the shape of the force peaks and the degree of cooperativity in the protein complex. Remarkably, we find that the degree of stabilization conferred by the interactions between units is determined by a combination between the stability of the interface and the internal fluctuations of a module.
This research has been supported by NSF CAREER Award MCB-0845002.
Ruxandra I. Dima
Department of Chemistry