T-cell epitope prediction and immune complex simulation using molecular dynamics: state of the art and persisting challenges

Abstract

Atomistic Molecular Dynamics provides powerful and flexible tools for the prediction and analysis of molecular and macromolecular systems. Specifically, it provides a means by which we can measure theoretically that which cannot be measured experimentally: the dynamic time-evolution of complex systems comprising atoms and molecules. It is particularly suitable for the simulation and analysis of the otherwise inaccessible details of MHC-peptide interaction and, on a larger scale, the simulation of the immune synapse. Progress has been relatively tentative yet the emergence of truly high-performance computing and the development of coarse-grained simulation now offers us the hope of accurately predicting thermodynamic parameters and of simulating not merely a handful of proteins but larger, longer simulations comprising thousands of protein molecules and the cellular scale structures they form. We exemplify this within the context of immunoinformatics.

Figure 1

A thermodynamic cycle for free energy calculation. AB, A′B and A, A′ are the bound and unbound states of two different, but similar molecules (shown here as peptides p1 and p2 complexed with MHC) binding with the same molecule B (shown as TCR). Here and are the binding free energies of A and A′ to B, while and are the free energy differences between the two molecules in their bound and unbound states, respectively. The vertical legs above are ‘alchemical’ paths which transform one molecule into another, while the horizontal legs are ‘chemical’ paths which describe the binding process of one molecule to another.

Figure 2

the escalating scale necessary to simulate large-scale immunological phenomenon. (A) Model of the MHC alone, equivalent in size to the simulation undertaken in [150]. (B) Model of the MHC complexed to the TCR, equivalent in size to the simulations undertaken in [151]. (C) Complete model of a unit of the immune synapse, comprising MHC, TCR, peptide, CD4, and two opposing sections of membrane, as simulated in [141].

Figure 3

Schematic of an ITC experiment. Evolution of an ITC experiment; each arrow indicates a separate injection of ligand.

Figure 4

Simulating the Immune synapse. (A) A detailed molecular model used for the initial simulation of the immune synapse comprising CD4, peptide-MHC, TCR, and membrane regions [141]. (B) The same model as in (A), but this time it is shown fully solvated.