Quantum chemical calculations predict biological function: the case of T cell receptor interaction with a peptide/MHC class I

Abstract

A combination of atomic correlation statistics and quantum chemical calculations are shown to predict biological function. In the present study, various antigenic peptide-Major Histocompatibility Complex (pMHC) ligands with near-identical stereochemistries, in complexation with the same T cell receptor (TCR), were found to consistently induce distinctly different quantum chemical behavior, directly dependent on the peptide's electron spin density and intrinsically expressed by the protonation state of the peptide's N-terminus. Furthermore, the cumulative coordination difference of any variant in respect to the native peptide was found to accurately reflect peptide biological function and immerges as the physical observable which is directly related to the immunological end-effect of pMHC-TCR interaction.

Atomic Coordination Reflects Peptide Immunogenicity

“…The total and partial PDF of unprotonated peptide structures are shown in Figures 2A–D . The peak positions in every PDF curve underpinned our previously discussed theme of bond length uniformity within the first coordination shell (Antipas and Germenis, 2015a , b ), the latter extending up to approximately 1.6 Å as indicated by the total PDF datasets. More precisely, the first coordination shell primarily comprised C-C and C-N bonded interactions, which were respectively 1.5 and 1.3 Å in length, regardless of the peptide (bond lengths are rounded up to a single decimal point).…”

“…All complexes were presented by HLA-A201 and were bound to the human A6TCR (Ding et al, 1999 ); furthermore, all complexes have been functionally characterized by cell assays as well as by kinetic and thermodynamic measurements (Ding et al, 1999 ). In alignment to previous work of ours (Antipas and Germenis, 2015a , b ), the current analysis has been performed in the gas phase. The assumption of absence of water molecules from the cleft is reasonable on the basis of a reported entropic advantage (Schamel and Reth, 2007 ).…”

“…We also took into account the possibility of charge and spin on peptide structure by calculating the electronic structure for a range of allowed spin multiplicities up to the quintet state. A complete set of charge and spin polarization conditions is given in our precursor work (Antipas and Germenis, 2015a , b ). All peptides were assumed to experience a neutral pH; furthermore, all protonated structures were initially zwitterionic and two different sets of ab initio calculations were carried out.…”

“…Coordination refers to atomic structure and expresses the tendency of atoms to be surrounded by other atoms (the coordination number indicates the number of atoms surrounding a reference atom). The calculation of atomic coordination is based on the initial formulation of a histogram of interatomic interactions, via calculation of the distances between all atom pairs and the assignment of these distances to bins of a predefined size (e.g., 0.1 Å; choice of the most appropriate bin size is a matter of experimentation (Antipas and Germenis, 2015a , b , c , d ) but does not affect the results if chosen to be sufficiently small). By convention, the ith bin is assigned all interatomic distances, R, within the range r < R < r + Δr, where r = i * Δ r and Δr is the bin size.…”

“…Previously we suggested that biological function may not be predicted based on energetics (Antipas and Germenis, 2015a , b ), as all bonded (and indeed, certain non-bonded) interactions occur within the first coordination shell of short range order; in the same work we argued that, due to the uniformity of bond lengths (which are directly correlated to bond energies) across the entirety of protein tertiary structure, binding energetics will tend to be degenerate. Here, we will exemplify this claim for the case of the Tax antigen (Tanaka et al, 2010 )—a transcriptional regulatory protein of the human T-cell leukemia virus posing an attractive target for anti-cancer vaccine development (Sundaram et al, 2003 ) due to its critical role in HTLV-1-associated leukemogenesis (Kannagi et al, 1991 ; Elovaara et al, 1993 ; Pique et al, 2000 )—and three of its artificially synthesized variants (Ding et al, 1999 ) by additionally showing that coordination carries the “signature” of peptide immunological identity.…”