New force replica exchange method and protein folding pathways probed by force-clamp technique

Abstract

We have developed a new extended replica exchange method to study thermodynamics of a system in the presence of external force. Our idea is based on the exchange between different force replicas to accelerate the equilibrium process. We have shown that the refolding pathways of single ubiquitin depend on which terminus is fixed. If the N-end is fixed then the folding pathways are different compared to the case when both termini are free, but fixing the C-terminal does not change them. Surprisingly, we have found that the anchoring terminal does not affect the pathways of individual secondary structures of three-domain ubiquitin, indicating the important role of the multi-domain construction. Therefore, force-clamp experiments, in which one end of a protein is kept fixed, can probe the refolding pathways of a single free-end ubiquitin if one uses either the poly-ubiquitin or a single domain with the C-terminus anchored. However, it is shown that anchoring one end does not affect refolding pathways of the titin domain I27, and the force-clamp spectroscopy is always capable to predict folding sequencing of this protein. We have obtained the reasonable estimate for unfolding barrier of ubiqutin. The linkage between residue Lys48 and the C-terminal of ubiquitin is found to have the dramatic effect on the location of the transition state along the end-to-end distance reaction coordinate, but the multi-domain construction leaves the transition state almost unchanged. We have found that the maximum force in the force-extension profile from constant velocity force pulling simulations depends on temperature nonlinearly. However, for some narrow temperature interval this dependence becomes linear, as have been observed in recent experiments.

37 pages, 1 table, 11 figures, accepted for publication in JCP

References in corpus (9)

• Exchange Monte Carlo Method and Application to Spin Glass Simulations
• An Ising-Like model for protein mechanical unfolding
• Effect of finite size on cooperativity and rates of protein folding
• Finite size effects on thermal denaturation of globular proteins
• Refolding upon force quench and pathways of mechanical and thermal unfolding of ubiquitin
• Folding of the Protein Domain hbSBD
• Internal protein dynamics shifts the distance to the mechanical transition state
• Protein folding in a force-clamp
• Finite size effects on calorimetric cooperativity of two-state proteins

Cited by in corpus (7)

• Mechanical unfolding and refolding pathways of ubiquitin
• Dependence of protein mechanical unfolding pathways on pulling speeds
• Role of loop entropy in the force induced melting of DNA hairpin
• Combining Coarse-Grained Protein Models with Replica-Exchange All-Atom Molecular Dynamics
• A structure-based model fails to probe the mechanical unfolding pathways of the titin I27 domain
• Role of pulling direction in understanding the energy landscape of proteins
• New method for deciphering free energy landscape of three-state proteins