Beneficent and Maleficent Effects of Cations on Bufadienolide Binding to Na⁺,K⁺-ATPase

Abstract

Kinetic properties and crystal structures of the Na + ,K + -ATPase in complex with cardiotonic steroids (CTS) revealed significant differences between CTS subfamilies (Laursen et al.). Thus, we found beneficial effects of K + on bufadienolide binding, which strongly contrasted with the well-known antagonism between K + and cardenolides. In order to understand this peculiarity of bufalin interactions, we used docking and molecular dynamics simulations of the complexes involving Na + ,K + -ATPase, bufadienolides (bufalin, cinobufagin), and ions (K + , Na + , Mg 2+ ). The results revealed that bufadienolide binding is affected by (i) electrostatic attraction of the lactone ring by a cation and (ii) the ability of a cation to stabilize and "shape" the site constituted by transmembrane helices of the αsubunit (αM1−6). The latter effect was due to varying coordination patterns involving amino acid residues from helix bundles αM1−4 and αM5−10. Substituents on the steroid core of a bufadienolide add to and modify the cation effects. The above rationale is fully consistent with the ion effects on the kinetics of Na + ,K + -ATPase/bufadienolide interactions.

Effects of Bufadienolides from Bufo viridis Toad Venom on Blood Biochemical Compositions and Thromboelastographic Parameters

“…Taking the high cardiotropic effects of bufadienolides [21,22,23] into consideration, we studied their effects on general toxicology with the purpose of possible implementation into medical practice as a cardiotropic drug. Therefore, our upcoming experiments were dedicated to investigating the influence on some biochemical parameters such as total protein, alanine aminotransferase, aspartate aminotransferase, cholesterol, glucose, and urea in the blood of rabbits.…”

Advanced Electrostatic Model for Monovalent Ions Based on Ab Initio Energy Decomposition

“…The Drude polarizable FF has been parametrized in conjunction with SWM4-NDP water for atomic and molecular ions. , Ion LJ parameters were tuned to reproduce QM ion–water interaction energy and experimental hydration free energy (HFE). The AMOEBA polarizable FF for atomic ions has also been developed by using a similar approach. , These ion models have been used to study a variety of biological problems, such as ion permeation in membrane channels, ATPases, and ion selectivity in proteins…”