Final Report Summary - EASTFE3 (Efficient and accurate simulation techniques for free energies, enthalpies and entropies)
The project focused on the efficient and accurate calculation of free energies, enthalpies and entropies. In the context of this project, various new methods have been developed and applied to relevant biomolecular systems. Three research lines were defined concerning separate, but related topics.
Research line 1 focused on the efficient calculation of free energies. By separating the nonpolar and polar contributions to the free energy, the strengths of different methods could be used. For the nonpolar contribution, the one-step perturbation approach is excellently suited, while for the polar contributions, various end-state methods were used, that started from a linear response approximation. Careful inspection of the free energy changes lead to the observation that the linearity these methods assume is often not given, leading to the definition of a new third-power fitting approach, which includes curvature in the free-energy profile of charging processes, without the need for additional simulations. These methods have been applied to various biomolecular systems and could be applied in drug design projects.
Research line 2 focused on the calculation of enthalpic and entropic constributions to the free energy and the dissection of these thermodynamic quantities into parts that seem to truly drive the processes and parts that are exactly compensated in the free energy and therefore do not contribute significantly to the free energy difference. In the context of drug design, this has lead to additional insight into the effects of enthalpy-entropy compensation. We have first described our methods on a toy system, and subsequently applied the methods to two larger protein-ligand systems. The first being the Cytochrome P450 enzyme, of which a mutant shows stereospecific binding of propranolol. The second involved allosteric inhibitors of the glutamate receptor and led to a collaborative publication with a group performing the actual experimental drug design.
Research line 3 focused on the further development of enhanced sampling techniques. One aspect of this research line was involved with finding the path by which a ligand finds it way into the protein. Without a priori knowledge about the binding path, sampling reversible binding can be difficult to achieve. To alleviate this problem, we introduced the distancefield as a reaction coordinate for such calculations. The distancefield is a grid-based method in which the shortest distance between the binding site and a ligand is determined, avoiding routes that pass through the protein. Combining this reaction coordinate with Hamiltonian replica exchange molecular dynamics allows for the reversible binding of the ligand to the protein. Furthermore, we have used local elevation techniques together with free-energy calculations to enhance the sampling of conformational changes along alchemical changes or in the context of the methods established in research line 1.
Overall, the project has contributed tremendously to the establishment of our research group at the host institution, in Austria and internationally.
Research line 1 focused on the efficient calculation of free energies. By separating the nonpolar and polar contributions to the free energy, the strengths of different methods could be used. For the nonpolar contribution, the one-step perturbation approach is excellently suited, while for the polar contributions, various end-state methods were used, that started from a linear response approximation. Careful inspection of the free energy changes lead to the observation that the linearity these methods assume is often not given, leading to the definition of a new third-power fitting approach, which includes curvature in the free-energy profile of charging processes, without the need for additional simulations. These methods have been applied to various biomolecular systems and could be applied in drug design projects.
Research line 2 focused on the calculation of enthalpic and entropic constributions to the free energy and the dissection of these thermodynamic quantities into parts that seem to truly drive the processes and parts that are exactly compensated in the free energy and therefore do not contribute significantly to the free energy difference. In the context of drug design, this has lead to additional insight into the effects of enthalpy-entropy compensation. We have first described our methods on a toy system, and subsequently applied the methods to two larger protein-ligand systems. The first being the Cytochrome P450 enzyme, of which a mutant shows stereospecific binding of propranolol. The second involved allosteric inhibitors of the glutamate receptor and led to a collaborative publication with a group performing the actual experimental drug design.
Research line 3 focused on the further development of enhanced sampling techniques. One aspect of this research line was involved with finding the path by which a ligand finds it way into the protein. Without a priori knowledge about the binding path, sampling reversible binding can be difficult to achieve. To alleviate this problem, we introduced the distancefield as a reaction coordinate for such calculations. The distancefield is a grid-based method in which the shortest distance between the binding site and a ligand is determined, avoiding routes that pass through the protein. Combining this reaction coordinate with Hamiltonian replica exchange molecular dynamics allows for the reversible binding of the ligand to the protein. Furthermore, we have used local elevation techniques together with free-energy calculations to enhance the sampling of conformational changes along alchemical changes or in the context of the methods established in research line 1.
Overall, the project has contributed tremendously to the establishment of our research group at the host institution, in Austria and internationally.