Unbinding and unfolding of adhesion protein complexes through stretching: Interplay between shear and tensile mechanical clamps

Abstract

Using coarse-grained molecular dynamics simulations, we analyze mechanically induced dissociation and unfolding of the protein complex CD48-2B4. This heterodimer is an indispensable component of the immunological system: 2B4 is a receptor on natural killer cells whereas CD48 is expressed on surfaces of various immune cells. So far, its mechanostability has not been assessed either experimentally or theoretically. We find that the dissociation processes strongly depend on the direction of pulling and may take place in several pathways. Interestingly, the CD48-2B4 interface can be divided into three distinct patches that act as units when resisting the pulling forces. At experimentally accessible pulling speeds, the characteristic mechanostability forces are in the range between 100 and 200 pN, depending on the pulling direction. These characteristic forces need not be associated with tensile forces involved in the act of separation of the complex because prior shear-involving unraveling within individual proteins may give rise to a higher force peak.

Structural entanglements in protein complexes

“…The secondary structures of 2EFV consists of four helices (23-32, 41-49, 62-71, 74-86), two 3-10 helices (33-35, 72-73), and two β -strands (12)(13)(14)(15)(16)(17)(54)(55)(56)(57)(58)(59). The knot is of the trefoil type and its ends are located at sites 11 and 73.…”

Mechanical Unfolding of Proteins—A Comparative Nonequilibrium Molecular Dynamics Study

“…Coarse-grained simulations are performed using a structure-based model ( 28 , 29 , 30 , 31 ) with single amino acid resolution and interaction centers located on each amino acid’s C α atom. Peptide bonds connecting consecutive residues are simulated by a harmonic potential, with additional terms promoting native local chirality of the chain ( 32 ).…”

Citrate synthase proteins in extremophilic organisms: Studies within a structure-based model

“…To study thermodynamic properties of the CS dimers, we performed overdamped Langevin dynamics simulations using in-house software 15,42 . The simulations were carried out at 31 different temperatures T distributed uniformly in the interval from 0.1 ǫ/k B to 0.7 ǫ/k B .…”

“…[7][8][9][10][11][12] ). They are not equivalent, but their predictions are expected to be most accurate in a vicinity of the native state -a situation encountered, for instance, during stretching manipulations [13][14][15][16] . It has also been argued that protein folding processes may be proceeding as in the Go-like models due to minimization of hindrances to folding [17][18][19][20][21][22] .…”