Potential-energy and free-energy surfaces of glycyl-phenylalanyl-alanine (GFA) tripeptide: Experiment and theory

The free-energy surface (FES) of glycyl-phenylalanyl-alanine (GFA) tripeptide was explored by molecular dynamics (MD) simulations in combination with high-level correlated ab initio quantum chemical calculations and metadynamics. Both the MD and metadynamics employed the tight-binding DFT-D method instead of the AMBER force field, which yielded inaccurate results. We classified the minima localised in the FESs as follows: a) the backbone-conformation at arrangement; and b) the existence of a CCOH center dot center dot center dot OC intramolecular H-bond (families CO2Hfree and CO2Hbonded). Comparison with experimental results showed that the most stable minima in the FES correspond to the experimentally observed structures. Remarkably, however, we did not observe experimentally the CO2Hbonded family (also predicted by metadynamics), although its stability is comparable to that of the CO2Hfee structures. This fact was explained by the former's short excitedstate lifetime. We also carried out ab initio calculations using DFT-D and the M06-2X functional. ne importance of the dispersion energy in stabilising peptide conformers is well reflected by our pioneer analysis using the DFT-SAPT method to explore the nature of the backbone/side-chain interactions.