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

Ground State of the Easy-Axis Rare-Earth Kagom\'e Langasite Pr3_3Ga5_5SiO14_{14}

We report muon spin relaxation ($\mu$SR) and $^{69,71}$Ga nuclear quadrupolar resonance (NQR) local-probe investigations of the kagom\'e compound Pr$_3$Ga$_5$SiO$_{14}$. Small quasi-static random internal fields develop below 40 K and persist down to our base temperature of 21 mK. They originate from hyperfine-enhanced $^{141}$Pr nuclear magnetism which requires a non-magnetic Pr$^{3+}$ crystal-field (CF) ground state. Besides, we observe a broad maximum of the relaxation rate at $\simeq 10$ K which we attribute to the population of the first excited magnetic CF level. Our results yield a Van-Vleck paramagnet picture, at variance with the formerly proposed spin-liquid ground state.Comment: minor change