TY - JOUR
T1 - Combining Machine Learning and Enhanced Sampling Techniques for Efficient and Accurate Calculation of Absolute Binding Free Energies
AU - Evans, Rhys
AU - Hovan, Ladislav
AU - Tribello, Gareth
AU - Cossins, Benjamin
AU - Estarellas, Carolina
AU - Gervasio, Francesco
PY - 2020/5/19
Y1 - 2020/5/19
N2 - Calculating absolute binding free energies is challenging and important. In this paper, we test some recently-developed metadynamics-based methods and develop a new combination with a Hamiltonian replica-exchange approach. The methods were tested on 18 chemically-diverse ligands with a wide range of different binding affinities to a complex target; namely, human soluble epoxide hydrolase. The results suggest that metadynamics with a funnel-shaped restraint can be used to calcu-late, in a computationally affordable and relatively accurate way, the absolute binding free energy for small fragments. When used in combination with an optimal path-like variable obtained using machine learning; or with the Hamiltonian replica-exchange algorithm SWISH; this method can achieve reasonably accurate results for increasingly complex ligands, with a good balance of computational cost and speed. An additional benefit of using the combination of metadynamics and SWISH is that it also provides useful information about the role of water in the binding mechanism.
AB - Calculating absolute binding free energies is challenging and important. In this paper, we test some recently-developed metadynamics-based methods and develop a new combination with a Hamiltonian replica-exchange approach. The methods were tested on 18 chemically-diverse ligands with a wide range of different binding affinities to a complex target; namely, human soluble epoxide hydrolase. The results suggest that metadynamics with a funnel-shaped restraint can be used to calcu-late, in a computationally affordable and relatively accurate way, the absolute binding free energy for small fragments. When used in combination with an optimal path-like variable obtained using machine learning; or with the Hamiltonian replica-exchange algorithm SWISH; this method can achieve reasonably accurate results for increasingly complex ligands, with a good balance of computational cost and speed. An additional benefit of using the combination of metadynamics and SWISH is that it also provides useful information about the role of water in the binding mechanism.
U2 - 10.1021/acs.jctc.0c00075
DO - 10.1021/acs.jctc.0c00075
M3 - Article
SN - 1549-9618
JO - Journal of Chemical Theory and Computation
JF - Journal of Chemical Theory and Computation
ER -