Investigation of many-body effects in the kernel of hemoglobin for ligand binding

Metalloporphyrin systems, such as heme, play a central role in biochemistry. The ability of such molecules to reversibly bind small ligands is vital for life, particularly in heme, which can bind diatomic molecules such as O2 and CO. Crucially, heme is the primary transport molecule in human respiration, but whereas O2 binds reversibly, CO binds irreversibly!

Recent work soon to appear in Physical Review Letters, by Cedric Weber, David O'Regan and others, used LS-DFT+DMFT (Linear-Scaling Density Functional Theory + Dynamical Mean-Field Theory, using ONETEP) to study the binding of oxygen and carbon monoxide to the heme molecule. They found that the many-body ground-state is entangled, and that a 3d orbital-selection process occurs beyond a critical value of the Hund's exchange coupling parameter J, by which out-of-plane orbital hybridization is enhanced and the difference of ligand binding affinities is strongly reduced. This work offers a very detailed picture of the microscopic mechanisms of diatomic ligand binding to heme, and is among the first applications of DFT+DFMT to molecules, including total-energies, spectral properties in very good agreement with experiment, and transient magnetic response calculations.


Investigation of protein-protein interactions with ONETEP

Biomolecular assemblies such as protein-protein complexes are crucial functional components of the cell and are essential for many processes such as for example the synthesis of proteins from messenger RNA by the ribosome, or the repair of breaks in the DNA by the complex between the BRCA2 and RAD51 proteins. With ONETEP researchers in Cambridge and Southampton have been able to study the entire complex between human RAD51 and BRCA2 elucidating the mechanism of interaction in terms of the location and strength of "energetic hotspots", which are amino-acids that contribute the bulk of the stabilisation during binding. Furthermore, by performing natural bond orbital (NBO) analysis on the density matrix from the ONETEP calculations they have found that hyperconjugative interactions between non-bonding electron pairs and antibonding pi* NBOs provide a hitherto unknown stabilization mechanism for the protein conformation that leads to maximum interaction between the energetic hotspots. The ability to study processes at protein-protein interfaces opens up new ways of probing chemical and physical processes that happen inside the cell.

Electron density polarisation at the interface between RAD51 and the BRC4 domain of BRCA2

Towards drug optimisation with ONETEP

The computational simulation of the strength with which drugs bind to proteins and other biomolecular entities can offer important cost-saving guidance at the early stages of the drug development process. Typically such simulations are performed with classical force fields. The empirical nature of force fields often means that interactions may not be represented with the required accuracy, especially for new drug candidates which may lie outside the function or parameter space that was used to generate the force field. Researchers in Southampton in collaboration with researhers in Boehringer Ingelheim and Accelrys have been using calculations with ONETEP on entire protein-drug complexes in order to obtain more accurate interactions and better estimates of free energies of receptor-drug binding. This work goes hand in hand with other recent and ongoing developments in ONETEP such as dispersion interactions, solvent effects, electrostatic embedding, ab initio molecular dynamics, and statistical mechanics techniques for obtaining free energies.

10151-atom calculation with ONETEP on the complex of the T4 Lysozyme L99A/M102Q protein and ligand in water and counterions.