Catalytic Mechanism of the Maltose Transporter Hydrolyzing ATP

We use quantum mechanical and molecular mechanical (QM/MM) simulations to study ATP hydrolysis catalyzed by the maltose transporter. This protein is a prototypical member of a large family that consists of ATP-binding cassette (ABC) transporters. The ABC proteins catalyze ATP hydrolysis to perform a variety of biological functions. Despite extensive research efforts, the precise molecular mechanism of ATP hydrolysis catalyzed by the ABC enzymes remains elusive. In this work, the reaction pathway for ATP hydrolysis in the maltose transporter is evaluated using a QM/MM implementation of the nudged elastic band method without presuming reaction coordinates. The potential of mean force along the reaction pathway is obtained with an activation free energy of 19.2 kcal/mol in agreement with experiments. The results demonstrate that the reaction proceeds via a dissociative-like pathway with a trigonal bipyramidal transition state in which the cleavage of the γ-phosphate P–O bond occurs and the O–H bond of the lytic water molecule is not yet broken. Our calculations clearly show that the Walker B glutamate as well as the switch histidine stabilizes the transition state via electrostatic interactions rather than serving as a catalytic base. The results are consistent with biochemical and structural experiments, providing novel insight into the molecular mechanism of ATP hydrolysis in the ABC proteins

Probing Cellular and Molecular Mechanisms of Cigarette Smoke-Induced Immune Response in the Progression of Chronic Obstructive Pulmonary Disease Using Multiscale Network Modeling

<div><p>Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder characterized by progressive destruction of lung tissues and airway obstruction. COPD is currently the third leading cause of death worldwide and there is no curative treatment available so far. Cigarette smoke (CS) is the major risk factor for COPD. Yet, only a relatively small percentage of smokers develop the disease, showing that disease susceptibility varies significantly among smokers. As smoking cessation can prevent the disease in some smokers, quitting smoking cannot halt the progression of COPD in others. Despite extensive research efforts, cellular and molecular mechanisms of COPD remain elusive. In particular, the disease susceptibility and smoking cessation effects are poorly understood. To address these issues in this work, we develop a multiscale network model that consists of nodes, which represent molecular mediators, immune cells and lung tissues, and edges describing the interactions between the nodes. Our model study identifies several positive feedback loops and network elements playing a determinant role in the CS-induced immune response and COPD progression. The results are in agreement with clinic and laboratory measurements, offering novel insight into the cellular and molecular mechanisms of COPD. The study in this work also provides a rationale for targeted therapy and personalized medicine for the disease in future.</p></div

CS-induced (S = 0.7) population dynamics.

<p>Dynamics of (a) T₈, T_g, T₁₇, T₂, and T₁, and (b) T_D.</p

CS-induced (S = 1.67) population dynamics.

<p>M₁, M₂ and D_C of dynamics over a time period of (a) 4000 days and (b) 180 days [the dashed square region in (a)].</p

I<i>n silico</i> knockout simulations.

<p>(a) T_D dynamics, (b) I_α dynamics, (c) I₆ dynamics, and (d) I₁₇ dynamics. I<i>n silico</i> knockouts of M1 (red dashed line), DC (red circles), Th1 (black stars), Th17 (black plus), CD8⁺T (black squares), TNF-α (blue dash-and-dot line), INF-γ (black asterisk), IL-6 (blue triangles), and IL-17 (black cross) [wild type is denoted by WT (black solid line)].</p

Network model for CS-induced immune response.

<p>Interactions between various nodes that represent cytokines, immune cells, and TD are described (for detailed description, see text).</p

Dynamics of T_D with different values of k₁₃ and effects of cigarette smoking cessation.

<p>(a) k₁₃< 2.6×10⁻² ml/(cell day) corresponds to resistant smokers (T_D<30%), while k₁₃≥2.6×10⁻² ml/(cell day) is associated with susceptible smokers. (b) Effects of smoking cessation after 2500 days of CS exposure. 2.6×10^-2ml/(cell day) ≤ k₁₃ < 0.31ml/(cell day) corresponds to reversible susceptible smokers and COPD is reversible. k₁₃≥0.31 ml/(cell day) is associated with severely susceptible smokers. In this case, COPD is not reversible.</p

CS-induced (S = 0.7) population dynamics.

<p>Dynamics of I_α, I₆, I₁₀, I_β, I_γ, I₁₇ and I₄ over a time period of (a) 4000 days and (b) 180 days [the dashed square region in (a)].</p

One of Loops 1, 2, 3, and 4 is activated while the others are broken.

<p><b>(</b>a) Loop 1, 2, or 4 alone causes CODP while Loop 3 does not. (b) As Loop 1 is activated, M₁ (red solid line) predominates over M₂ (red dashed line). While Loop 4 is activated, both M₁ (blue solid line) and M₂ (blue dashed line) are relatively low. (c) In the case where Loop 1 is activated, T_g is predominant over T₈ or T₁₇. (d) The activation of Loop 4 leads to the predominance of T₈ and T₁₇ over T_g.</p