Study of protein structural deformations under external mechanical perturbations by a coarse-grained simulation method

Abstract

The mechanical properties of biomolecules play pivotal roles in regulating cellular functions. For instance, extracellular mechanical stimuli are converted to intracellular biochemical activities by membrane receptors and their downstream adaptor proteins during mechanotransduction. In general, proteins favor the conformation with the lowest free energy. External forces modify the energy landscape of proteins and drive them to unfolded or deformed conformations that are of functional relevance. Therefore, the study of the physical properties of proteins under external forces is of fundamental importance to understand their functions in cellular mechanics. Here, a coarse-grained computational model was developed to simulate the unfolding or deformation of proteins under mechanical perturbation. By applying this method to unfolding of previously studied proteins or protein fragments with external forces, we demonstrated that our results are quantitatively comparable to previous experimental or all-atom computational studies. The model was further extended to the problem of elastic deformation of large protein complexes formed between membrane receptors and their ligands. Our studies of binding between T cell receptor (TCR) and major histocompatibility complex (MHC) illustrated that stretching of MHC ligand initially lowers its binding energy with TCR, supporting the recent experimental report that TCR/MHC complex is formed through the catch-bond mechanism. Finally, the method was, for the first time, applied to pulling of an eight-cadherin cluster that was formed by their trans and cis binding interfaces. Our simulation results show that mechanical properties of adherens junctions are functionally important to cell adhesion.

Integrating Experiment and Theory to Understand TCR-pMHC Dynamics

“…The atomic complexity of the system can be reduced significantly using coarse-grained (CG) methods in which groups of atoms are replaced by beads, allowing longer simulations at the cost of fine details (60). This approach is therefore useful for studying larger complexes such as TCR-pMHC in membrane (61) and TCR-pMHC-CD4 complexes (62). CG methods are complimentary to atomistic simulations and offer a feasible approach to tackling the combined challenges of large immune assemblies and long timescales associated with changes in membrane morphology.…”

A Computational Model for Kinetic Studies of Cadherin Binding and Clustering

“…For instance, recent studies showed that the cytoskeleton plays an important role in regulating the mechanical response of cellular junctions (67). In the future, we plan to extend this study by developing or applying various computational approaches (68) to understand the mechanical properties of cadherin clusters and the contribution of the cytoskeleton to these properties.…”

Computational studies of protein–protein dissociation by statistical potential and coarse-grained simulations: a case study on interactions between colicin E9 endonuclease and immunity proteins

“…To tackle this problem, protein complex formed between the E9 DNase domains of bacterial colicins and their immunity proteins are used as a test system. Our previously developed coarse-grained (CG) model [38] was extended to simulate the dissociation of the complex. In detail, two upgrades have been made.…”