T cells orchestrate adaptive, pathogen-specific immune responses. T cells have a surface receptor (called TCR) whose ligands are complexes (pMHCs) of peptides (derived from pathogens or host proteins) and major histocompatibility complex proteins (MHCs). MHC proteins vary between hosts. During organ transplants, host TCRs interact with peptides present in complex with genetically different MHCs. This usually causes a vigorous immune response: alloreactivity. Studies of alloreactive protein interactions have yielded results that present a puzzle. Some crystallographic studies concluded that the alloreactive TCR/MHC interface is essentially unaffected by changing the TCR peptide-binding region, suggesting that the peptide does not influence the interface. Another biochemical study concluded from mutation data that different peptides can alter the binding interface with the same TCR. To explore the origin of this puzzle, we used molecular dynamics simulations to study the dependence of the TCR/pMHC interface on changes in both the peptide and the TCR Our simulations show that the footprint of the TCR on the pMHC is insensitive to mutations of the TCR peptide-binding loops, but peptide mutations can make multiple local changes to TCR/pMHC contacts. Therefore, our results demonstrate that the structural and mutation data do not conflict and reveal how subtle, but important, characteristics of the alloreactive TCR/pMHC interface are influenced by the TCR and the peptide.