Structural variability and concerted motions of the T cell receptor – CD3 complex

Abstract

We investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) - CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al., Nature 573:546 (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR - CD3 complex, in particular in the EC interactions of the Cβ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR - CD3 complex revealed in our simulations provide atomistic insights for force-based models of TCR activation, which involve such structural changes in response to tilt-inducing forces on antigen-bound TCRs.

TCR-pMHC complex formation triggers CD3 dynamics

“…In the TCR-only system, in which the TCR EC folded over the CD3 co-receptors (Figure 1A), the TCR adopted predominantly bent conformations (smaller angles), with a peak in the distribution at 104°. Such bending was observed in previous simulations of the same starting structure (Pandey et al, 2021). In contrast, the TCRs in the TCR-pMHC system, for which the many interactions with CD3 were broken, tended to adopt an extended and open conformation (larger angles, with the peak of the distribution at 150°) where the TCR EC tilted away from the CD3 EC domains (Figure 4 and Figure 1B).…”

“…This observation raised the question of whether the angle between the TCR EC and transmembrane domain (TM) is dynamic. Molecular dynamics studies based on the complete TCR structure in a membrane demonstrated that the TCR is indeed flexible and that the TCR headgroup can adopt a range of different conformations (Prakaash et al, 2021; Pandey et al, 2021).…”

Structural variability and concerted motions of the T cell receptor – CD3 complex

“… The shading of the contact disks indicates the contact probability, that is the fraction of simulation structures in which the contact is present. The contact analysis is based on 120 × 50 = 6000 structures extracted at intervals of 10 ns from the second halves of the 120 μs-long trajectories, which reflect an equilibrated ensemble of simulation conformations (see Materials and methods) and are available at the Edmond Open Research Data Repository ( Pandey and Weikl, 2021 ). For clarity, only contacts with a contact probability larger than 0.5% are represented.…”

“…The contacts, contact numbers, and angles presented in Figures 2 and 3 are calculated from these 6000 structures. The 6000 structures are available at the Edmond Open Research Data Repository at https://dx.doi.org/10.17617/3.5m ( Pandey and Weikl, 2021 ).…”

Conformational ensemble of the full-length SARS-CoV-2 nucleocapsid (N) protein based on molecular simulations and SAXS data

“…Useful and appropriate tools for generating conformational ensembles of biomolecules are molecular dynamics (MD) simulations. However, despite steady developments in this field [ [23] , [24] , [25] ], all-atom MD simulations of multi-domain and partially disordered proteins are still challenging – not only because of the large sizes of such proteins but also because of the long time scales on which large conformational fluctuations occur. Coarse-grained molecular simulations, on the other hand, provide means to efficiently sample conformational ensembles of large, multi-domain and dynamic proteins and their complexes [ 4 , 20 , 26 ].…”