Relative Ligand-Binding Free Energies Calculated from Multiple Short QM/MM MD Simulations

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We have devised a new efficient approach to
compute combined quantum mechanical (QM) and molecular
mechanical (MM, i.e. QM/MM) ligand-binding relative free
energies. Our method employs the reference-potential
approach with free-energy perturbation both at the MM
level (between the two ligands) and from MM to QM/MM
(for each ligand). To ensure that converged results are
obtained for the MM → QM/MM perturbations, explicit
QM/MM molecular dynamics (MD) simulations are
performed with two intermediate mixed states. To speed up the calculations, we utilize the fact that the phase space can be extensively sampled at the MM level. Therefore, we run many short QM/MM MD simulations started from snapshots of the MM simulations, instead of a single long simulation. As a test case, we study the binding of nine cyclic carboxylate ligands to the octa-acid deep cavitand. Only the ligand is in the QM system, treated with the semiempirical PM6-DH+ method. We show that for eight of the ligands, we obtain well converged results with short MD simulations (1−15 ps). However, in one case, the convergence is slower (∼50 ps) owing to a mismatch between the conformational preferences of the MM and QM/MM potentials. We test the effect of initial minimization, the need of equilibration, and how many independent simulations are needed to reach a certain precision. The results show that the present approach is about four times faster than using standard MM → QM/MM free-energy perturbations with the same accuracy and precision.


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Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Teoretisk kemi
Sidor (från-till)3228
Antal sidor3237
TidskriftJournal of Chemical Theory and Computation
StatusPublished - 2018 maj 17
Peer review utfördJa


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