Thermodynamically consistent determination of free energies and rates in kinetic cycle models.

Kinetic and thermodynamic models of biological systems are commonly used to connect microscopic features to system function in a bottom-up multiscale approach. The parameters of such models-free energy differences for equilibrium properties and in general rates for equilibrium and out-of-equilibrium observables-have to be measured by different experiments or calculated from multiple computer simulations. All such parameters necessarily come with uncertainties so that when they are naively combined in a full model of the process of interest, they will generally violate fundamental statistical mechanical equalities, namely detailed balance and an equality of forward/backward rate products in cycles due to Hill.

Thermodynamically consistent determination of free energies and rates in kinetic cycle models.

Unlabelled: Kinetic and thermodynamic models of biological systems are commonly used to connect microscopic features to system function in a bottom-up multiscale approach. The parameters of such models-free energy differences for equilibrium properties and in general rates for equilibrium and out-of-equilibrium observables-have to be measured by different experiments or calculated from multiple computer simulations. All such parameters necessarily come with uncertainties so that when they are naively combined in a full model of the process of interest, they will generally violate fundamental statistical mechanical equalities, namely detailed balance and an equality of forward/backward rate products in cycles due to T.

Crystal structure of the Na/H antiporter NhaA at active pH reveals the mechanistic basis for pH sensing.

The strict exchange of protons for sodium ions across cell membranes by NaH exchangers is a fundamental mechanism for cell homeostasis. At active pH, Na/H exchange can be modelled as competition between H and Na to an ion-binding site, harbouring either one or two aspartic-acid residues. Nevertheless, extensive analysis on the model Na/H antiporter NhaA from Escherichia coli, has shown that residues on the cytoplasmic surface, termed the pH sensor, shifts the pH at which NhaA becomes active.

SAMPL6: calculation of macroscopic pK values from ab initio quantum mechanical free energies.

Macroscopic pK values were calculated for all compounds in the SAMPL6 blind prediction challenge, based on quantum chemical calculations with a continuum solvation model and a linear correction derived from a small training set. Microscopic pK values were derived from the gas-phase free energy difference between protonated and deprotonated forms together with the Conductor-like Polarizable Continuum Solvation Model and the experimental solvation free energy of the proton. pH-dependent microstate free energies were obtained from the microscopic pKs with a maximum likelihood estimator and appropriately summed to yield macroscopic pK values or microstate populations as function of pH.

Prediction of cyclohexane-water distribution coefficients for the SAMPL5 data set using molecular dynamics simulations with the OPLS-AA force field.

All-atom molecular dynamics simulations were used to predict water-cyclohexane distribution coefficients [Formula: see text] of a range of small molecules as part of the SAMPL5 blind prediction challenge. Molecules were parameterized with the transferable all-atom OPLS-AA force field, which required the derivation of new parameters for sulfamides and heterocycles and validation of cyclohexane parameters as a solvent. The distribution coefficient was calculated from the solvation free energies of the compound in water and cyclohexane.