Geometry Dynamics ofα-Helices in Different Class I Major Histocompatibility Complexes

Abstract

MHC α-helices form the antigen-binding cleft and are of particular interest for immunological reactions. To monitor these helices in molecular dynamics simulations, we applied a parsimonious fragment-fitting method to trace the axes of the α-helices. Each resulting axis was fitted by polynomials in a least-squares sense and the curvature integral was computed. To find the appropriate polynomial degree, the method was tested on two artificially modelled helices, one performing a bending movement and another a hinge movement. We found that second-order polynomials retrieve predefined parameters of helical motion with minimal relative error. From MD simulations we selected those parts of α-helices that were stable and also close to the TCR/MHC interface. We monitored the curvature integral, generated a ruled surface between the two MHC α-helices, and computed interhelical area and surface torsion, as they changed over time. We found that MHC α-helices undergo rapid but small changes in conformation. The curvature integral of helices proved to be a sensitive measure, which was closely related to changes in shape over time as confirmed by RMSD analysis. We speculate that small changes in the conformation of individual MHC α-helices are part of the intrinsic dynamics induced by engagement with the TCR.

CryoEM structures of anion exchanger 1 capture multiple states of inward- and outward-facing conformations

“…This elongation of a TM in a native protein has not been previously observed in any of the available IF structures of 7 + 7-fold transporters. Changes in the length or conformation of α-helices have previously been reported in the context of heparin induced activation of antithrombin, which is associated with a two-turn elongation of helix D in its C-terminus 45 , activation of the bacterial thermosensor DesK that involves elongation of its transmembrane helix 46 , and T cell receptor major histocompatibility complexes (MHC) interaction that involves MHC alpha helices conformational changes 47 . Folding/unfolding dynamics of α-helixes plays an important role in conformational transitions of proteins.…”

Prediction of Protein–Protein Interactions Between Alsin DH/PH and Rac1 and Resulting Protein Dynamics

“…Moreover, interesting regions were helix α3 and the following coiled region (α3-5) due to their observed dynamics and interaction with Rac1. Therefore, to evaluate the effect of the interaction between Rac1 and helix α6 (residues 865–895) on its straightness, the curvature of α6 axis on plane xz was analyzed as done previously ( Ribarics et al, 2015 ) ( Supplementary Material SM2 Section 3 ). Then, the effect of Rac1 interaction on α3 and α3-5 positions was described computing two quantities from representative snapshots extracted every 50 ps for both long and short replicas.…”

Intramolecular Domain Movements of Free and Bound pMHC and TCR Proteins: A Molecular Dynamics Simulation Study

“…Moreover, Macdonald et al [18] determined binding characteristics and immunogenicity of three MHC alleles (HLA-B*44:02, HLA-B*44:03, and HLA-B*44:05) in complex with the ABCD3 nine-mer peptide and the LC13 TCR and Ferber et al [19] analyzed TCR binding orientations over pMHC. In previous papers we used the 3KPS system for geometric analyses of alloreactive HLA α-helices [11,20] as well as for finding semi-rigid domains in MD simulations [21]. In the present study we consider differences in the dynamics of intramolecular domains between bound and unbound states of the 3KPS system.…”

“…Protein-protein interfaces within crystal structures of TCR-pMHC complexes have been evaluated in numerous studies and provided insight into the molecular mechanism behind the interaction and recognition mechanism of TCR with the pMHC [6,11,12] but lack information about the intermolecular approach and reorientation. Details of the binding and spatial rearrangements of the TCR-pMHC interaction on an atomistic scale remain to be uncovered.…”