Kinetic Monte Carlo Method for Rule-based Modeling of Biochemical Networks

We present a kinetic Monte Carlo method for simulating chemical transformations specified by reaction rules, which can be viewed as generators of chemical reactions, or equivalently, definitions of reaction classes. A rule identifies the molecular components involved in a transformation, how these components change, conditions that affect whether a transformation occurs, and a rate law. The computational cost of the method, unlike conventional simulation approaches, is independent of the number of possible reactions, which need not be specified in advance or explicitly generated in a simulation. To demonstrate the method, we apply it to study the kinetics of multivalent ligand-receptor interactions. We expect the method will be useful for studying cellular signaling systems and other physical systems involving aggregation phenomena.Comment: 18 pages, 5 figure

Protecting High Energy Barriers: A New Equation to Regulate Boost Energy in Accelerated Molecular Dynamics Simulations

Molecular dynamics (MD) is one of the most common tools in computational chemistry. Recently, our group has employed accelerated molecular dynamics (aMD) to improve the conformational sampling over conventional molecular dynamics techniques. In the original aMD implementation, sampling is greatly improved by raising energy wells below a predefined energy level. Recently, our group presented an alternative aMD implementation where simulations are accelerated by lowering energy barriers of the potential energy surface. When coupled with thermodynamic integration simulations, this implementation showed very promising results. However, when applied to large systems, such as proteins, the simulation tends to be biased to high energy regions of the potential landscape. The reason for this behavior lies in the boost equation used since the highest energy barriers are dramatically more affected than the lower ones. To address this issue, in this work, we present a new boost equation that prevents oversampling of unfavorable high energy conformational states. The new boost potential provides not only better recovery of statistics throughout the simulation but also enhanced sampling of statistically relevant regions in explicit solvent MD simulations

Differences between Midazolam and Propofol Sedation on Upper Airway Collapsibility Using Dynamic Negative Airway Pressure

Background: Upper airway obstruction (UAO) during sedation can often cause clinically significant adverse events. Direct comparison of different drugs' propensities for UAO may improve selection of appropriate sedating agents. The authors used the application of negative airway pressure to determine the pressure that causes UAO in healthy subjects sedated with midazolam or propofol infusions. Methods: Twenty subjects (12 male and 8 female) completed the study. After achieving equivalent levels of sedation, the subjects' ventilation, end-tidal gases, respiratory inductance plethysmographic signals, and Bispectral Index values were monitored for 5 min. Negative airway pressure was then applied via a facemask in steps of 3 cm H 2 O from ؊3 to ؊18 cm H 2 O. UAO was assessed by cessation of inspiratory airflow and asynchrony between abdomen and chest respiratory inductance plethysmographic signals. Results: Equivalent levels of sedation were achieved with both drugs with average (؎ SD) Bispectral Index levels of 75 ؎ 5. Resting ventilation was mildly reduced without any changes in end-tidal pressure of carbon dioxide. There was no difference between the drugs in the negative pressure resulting in UAO. Five female subjects and one male subject with midazolam and four female subjects and one male subject with propofol did not show any UAO even at ؊18 cm H 2 O. Compared with males, female subjects required more negative pressures to cause UAO with midazolam (P ‫؍‬ 0.02) but not with propofol (P ‫؍‬ 0.1). Conclusions: At the mild to moderate level of sedation studied, midazolam and propofol sedation resulted in the same propensity for UAO. In this homogeneous group of healthy subjects, there was a considerable range of negative pressures required to cause UAO. The specific factors responsible for the maintenance of the upper airway during sedation remain to be elucidated

The effects of hypo- and hyperglycaemia on the hypoxic ventilatory response in humans

Animal and tissue studies have indicated that the carotid bodies are sensitive to glucose concentrations within the physiological range. This glucose sensitivity may modulate the ventilatory response to hypoxia, with hyperglycaemia suppressing the hypoxic response and hypoglycaemia stimulating it. This study was designed to determine whether hypo- and hyperglycaemia modulate the hypoxic ventilatory response in humans. In 11 normal research participants, glucose levels were clamped at 2.8 and 11.2 mmol l−1 for 30 min. At the start and end of each clamp, blood was drawn for hormone measurement and the isocapnic hypoxic ventilatory response was measured. Because generation of reactive oxygen species may be a common pathway for the interaction between glucose and oxygen levels, the experiments were repeated with and without pretreatment for 1 week with vitamins C and E. Hypoglycaemia caused an increase in the counter-regulatory hormones, a 54% increase in isocapnic ventilation, and a 108% increase in the hypoxic ventilatory response. By contrast, hyperglycaemia resulted in small but significant increases in both ventilation and the hypoxic ventilatory response. Antioxidant vitamin pretreatment altered neither response. In conclusion, the stimulant effect of hypoglycaemia on the hypoxic ventilatory response is consistent with a direct effect on the carotid body, but an indirect effect through the activation of the counter-regulatory response cannot be excluded. The mechanisms behind the mild stimulating effect of hyperglycaemia remain to be elucidated