Thermodynamic integration network approach to ion transport through protein channels: Perspectives and limits.

We present a molecular dynamics simulation study of alkali metal cation transport through the double-helical and the head-to-head conformers of the gramicidin ion channel. Our approach is based on a thermodynamic integration network, which consists of a sequence of transport reactions, absolute free energies of solvation and cycles of alchemical transmutations of the ions. In this manner, we can reliably estimate free energies and their statistical errors via a least-squares method without imposing external forces on the system. Within the double helical channel, we find a free energy surface typical for hopping transport between isoenergetic sites of ion localization, separated by comparatively large activation barriers. For fast transport through the head-to-head conformation, the thermodynamic network scheme starts to break down. © 2018 Wiley Periodicals, Inc.

Simulating biological charge transfer: Continuum dielectric theory or molecular dynamics?

We study the thermodynamic parameters of Marcus's theory of charge transfer, the driving forces and the reorganization energies, using two widely applied approaches to bioenergetic problems that seem to be radically different: continuum dielectric theory via a numerical solution of Poisson's equation, and the thermodynamic integration approach based upon classical Newtonian molecular dynamics, as perfomed by Na et al., PCCP 19, 18,938 (2017). With application to a nitrite reductase NrfHA protein heterodimer, we obtain an excellent agreement between the respective driving forces with an r.m.s. deviation of 1.7 kcal/mol, and a lower limit to the reorganization energies. The computational methods turn out to be mutually supportive: molecular dynamics can be used to determine the parameters of a dielectric theory computation, which on the other hand can be used to properly rescale the reorganization energies and partition them into aqueous and protein contributions. In addition, we use the electrostatic approach to study the influence of Ca2+ ions on the free energy landscape of charge transfer.

Charge transfer through a fragment of the respiratory complex I and its regulation: an atomistic simulation approach.

We simulate electron transfer within a fragment of the NADH:ubiquinone oxidoreductase (respiratory complex I) of the hyperthermophilic bacterium Aquifex aeolicus. We apply molecular dynamics simulations, thermodynamic integration, and a thermodynamic network least squares analysis to compute two key parameters of Marcus' theory of charge transfer, the thermodynamic driving force and the reorganization energy. Intramolecular contributions to the Gibbs free energy differences of electron and hydrogen transfer processes, ΔG, are accessed by calibrating against experimental redox titration data. This approach permits the computation of the interactions between the species NAD+, FMNH2, N1a-, and N3-, and the construction of a free energy surface for the flow of electrons within the fragment. We find NAD+ to be a strong candidate for the regulation of charge transfer.

Thermodynamic integration network study of electron transfer: from proteins to aggregates.

We describe electron transfer through the NrfHA nitrite reductase heterodimer using a thermodynamic integration scheme based upon molecular dynamics simulations. From the simulation data, we estimate two of the characteristic energies of electron transfer, the thermodynamic driving forces, ΔG, and the reorganization energies, λ. Using a thermodynamic network analysis, the statistical accuracy of the ΔG values can be enhanced significantly. Although the reaction free energies and activation barriers are hardly affected by protein aggregation, the complete reaction mechanism only emerges from the simulations of the dimer rather than focussing on the individual protein chains: it involves an equienergetic transprotein element of electron storage and conductivity.

Rapid Response Systems Reduce In-Hospital Cardiopulmonary Arrest: A Pilot Study and Motivation for a Nationwide Survey.

BACKGROUND: Early recognition of the signs and symptoms of clinical deterioration could diminish the incidence of cardiopulmonary arrest. The present study investigates outcomes with respect to cardiopulmonary arrest rates in institutions with and without rapid response systems (RRSs) and the current level of cardiopulmonary arrest rate in tertiary hospitals. METHODS: This was a retrospective study based on data from 14 tertiary hospitals. Cardiopulmonary resuscitation (CPR) rate reports were obtained from each hospital to include the number of cardiopulmonary arrest events in adult patients in the general ward, the annual adult admission statistics, and the structure of the RRS if present. RESULTS: Hospitals with RRSs showed a statistically significant reduction of the CPR rate between 2013 and 2015 (odds ratio [OR], 0.731; 95% confidence interval [CI], 0.577 to 0.927; P = 0.009). Nevertheless, CPR rates of 2013 and 2015 did not change in hospitals without RRS (OR, 0.988; 95% CI, 0.868 to 1.124; P = 0.854). National university-affiliated hospitals showed less cardiopulmonary arrest rate than private university-affiliated in 2015 (1.92 vs. 2.40; OR, 0.800; 95% CI, 0.702 to 0.912; P = 0.001). High-volume hospitals showed lower cardiopulmonary arrest rates compared with medium-volume hospitals in 2013 (1.76 vs. 2.63; OR, 0.667; 95% CI, 0.577 to 0.772; P < 0.001) and in 2015 (1.55 vs. 3.20; OR, 0.485; 95% CI, 0.428 to 0.550; P < 0.001). CONCLUSIONS: RRSs may be a feasible option to reduce the CPR rate. The discrepancy in cardiopulmonary arrest rates suggests further research should include a nationwide survey to tease out factors involved in in-hospital cardiopulmonary arrest and differences in outcomes based on hospital characteristics.