Impact of pharmacologic interventions on peripheral artery disease.

Pharmacologic interventions are an integral component of peripheral artery disease (PAD) management, supported by high-quality clinical studies. Those affected by this potentially debilitating and life-threatening disease process often have multiple contributing conditions, such as tobacco abuse, diabetes, hypertension, and hyperlipidemia. In addition to medications aimed at improving claudication symptoms, risk factor modification and appropriate use of antiplatelet agents are essential to decreasing rates of major adverse clinical events and improving vessel patency following intervention. While lower extremity PAD is increasingly recognized as a prevalent condition, affected individuals remain undertreated with optimal pharmacotherapy. Novel approaches to treatment of PAD include stem cell therapy, which may play a beneficial role in those with minimal revascularization options but disease placing them at high risk for limb amputation. Additionally, timely initiation of optimal pharmacotherapy represents a cost-effective approach to management of this chronic condition.

Slow conformational motions that favor sub-picosecond motions important for catalysis.

It has been accepted for many years that functionally important motions are crucial to binding properties of ligands in such molecules as hemoglobin and myoglobin. In enzymatic reactions, theory and now experiment are beginning to confirm the importance of motions on a fast (ps) time scale in the chemical step of the catalytic process. What is missing is a clear physical picture of how slow conformational fluctuations are related to the fast motions that have been identified as crucial. This paper presents a theoretical analysis of this issue for human heart lactate dehydrogenase. We will examine how slow conformational motions bring the system to conformations that are distinguished as catalytically competent because they favor specific fast motions.

Ligand binding and protein dynamics in lactate dehydrogenase.

Recent experimental studies suggest that lactate dehydrogenase (LDH) binds its substrate via the formation of a LDH/NADH.substrate encounter complex through a select-fit mechanism, whereby only a minority population of LDH/NADH is binding-competent. In this study, we perform molecular dynamics calculations to explore the variations in structure accessible to the binary complex with a focus on identifying structures that seem likely to be binding-competent and which are in accord with the known experimental characterization of forming binding-competent species. We find that LDH/NADH samples quite a range of protein conformations within our 2.148 ns calculations, some of which yield quite facile access of solvent to the active site. The results suggest that the mobile loop of LDH is perhaps just partially open in these conformations and that multiple open conformations, yielding multiple binding pathways, are likely. These open conformations do not require large-scale unfolding/melting of the binary complex. Rather, open versus closed conformations are due to subtle protein and water rearrangements. Nevertheless, the large heat capacity change observed between binding-competent and binding-incompetent can be explained by changes in solvation and an internal rearrangement of hydrogen bonds. We speculate that such a strategy for binding may be necessary to get a ligand efficiently to a binding pocket that is located fairly deep within the protein's interior.