87 research outputs found
Absolute FKBP binding affinities obtained via non-equilibrium unbinding simulations
We compute absolute binding affinities for two ligands bound to the FKBP
protein using non-equilibrium unbinding simulations. The methodology is
straight-forward, requiring little or no modification to many modern molecular
simulation packages. The approach makes use of a physical pathway, eliminating
the need for complicated alchemical decoupling schemes. Results of this study
are promising. For the ligands studied here the binding affinities are
typically estimated within less than 4.0 kJ/mol of the target values; and the
target values are within less than 1.0 kJ/mol of experiment. These results
suggest that non-equilibrium simulation could provide a simple and robust means
to estimate protein-ligand binding affinities.Comment: 9 pages, 3 figures (no necessary color). Changes made to methodology
and results between revision
Resolution exchange simulation
We extend replica exchange simulation in two ways, and apply our approaches
to biomolecules. The first generalization permits exchange simulation between
models of differing resolution -- i.e., between detailed and coarse-grained
models. Such ``resolution exchange'' can be applied to molecular systems or
spin systems. The second extension is to ``pseudo-exchange'' simulations, which
require little CPU usage for most levels of the exchange ladder and also
substantially reduces the need for overlap between levels. Pseudo exchanges can
be used in either replica or resolution exchange simulations. We perform
efficient, converged simulations of a 50-atom peptide to illustrate the new
approaches.Comment: revised manuscript: 4.2 pages, 3 figure
Simple estimation of absolute free energies for biomolecules
One reason that free energy difference calculations are notoriously difficult
in molecular systems is due to insufficient conformational overlap, or
similarity, between the two states or systems of interest. The degree of
overlap is irrelevant, however, if the absolute free energy of each state can
be computed. We present a method for calculating the absolute free energy that
employs a simple construction of an exactly computable reference system which
possesses high overlap with the state of interest. The approach requires only a
physical ensemble of conformations generated via simulation, and an auxiliary
calculation of approximately equal central-processing-unit (CPU) cost.
Moreover, the calculations can converge to the correct free energy value even
when the physical ensemble is incomplete or improperly distributed. As a "proof
of principle," we use the approach to correctly predict free energies for test
systems where the absolute values can be calculated exactly, and also to
predict the conformational equilibrium for leucine dipeptide in implicit
solvent.Comment: To appear in J. Chem. Phys., 10 pages, 6 figure
Equilibrium Sampling From Nonequilibrium Dynamics
We present some applications of an Interacting Particle System (IPS)
methodology to the field of Molecular Dynamics. This IPS method allows several
simulations of a switched random process to keep closer to equilibrium at each
time, thanks to a selection mechanism based on the relative virtual work
induced on the system. It is therefore an efficient improvement of usual
non-equilibrium simulations, which can be used to compute canonical averages,
free energy differences, and typical transitions paths
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