HEME transfer

Hb to NEAT domain HEME transfer


Calcium Ion Channel

AMPA Receptor

Gating and mechanisms of channel activation and deactivation

NMDA Receptor

Mechanism of divalent ion selectivity - Mechanism of transmembrane domain (TMD) pore opening

Free Energy Calculation in Biological Systems

Enhanced sampling methods for free energy calculations of ions in membrane proteins


Transient receptor potential (TRP) channels function as sensors for various physical and chemical stimuli and are vitally important players in regulation of key biochemical processes in a variety of cells. TRPV5 and TRPV6 subtypes of TRP channels are the main Ca2+ entry channels in epithelia Their pores are selective for Ca2+ and permeable for a variety of monovalent and divalent cations. An exact mechanism of Ca2+ permeation and selectivity through the TRPV5/6 ion channels is unknown. Recently, a crystal structure of the TRPV6 channel, the first high-resolution structure of a TRP channel, has been solved in complex with different ions bound in the channel pore [1]. Analysis of the structure suggested that Ca2+ permeates TRPV6 channel by a knock-off mechanism. We have created a fully atomistic model of the trans-membrane (TM) domain of the TRPV6 channel in lipid and water, and performed molecular dynamics simulations of Na+ , Ca2+, Ba2+ , and Gd3+ ion permeation through the selectivity filter of this channel. As a result, our MD simulations directly demonstrate the key features of ion permeation through TRPV6 channel pore. In particular, at low calcium concentrations, we observed interplay of Na+ and Ca2+ permeation that follows the knock-off mechanism. We also compare Ca2+ permeation with permeation of Ba 2+ and channel block by Gd3+.

1. Saotome, Kei, Singh, A. K., Yelshanskaya, M. V., Sobolevsky, A. I. (2016) Crystal structure of the epithelial calcium channel TRPV6. Nature 534, 506-511

  • HEME transfer

    Red blood cell hemolysis in sickle cell disease (SCD) releases free hemoglobin. Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. We propose an approach that helps to eliminate extracellular hemoglobin toxicity in SCD by employing a bacterial protein system that evolved to extract heme from extracellular hemoglobin. NEAr heme Transporter (NEAT) domains from iron-regulated surface determinant proteins from Staphylococcus aureus specifically bind free heme as well as facilitate its extraction from hemoglobin. We demonstrate that a purified NEAT domain fused with human haptoglobin β-chain is able to remove heme from hemoglobin and reduce heme content and peroxidase activity of hemoglobin. We further use molecular dynamics (MD) simulations to resolve molecular pathway of heme transfer from hemoglobin to NEAT, and to elucidate molecular mechanism of such heme transferring process. Our study is the first of its kind, in which simulations are employed to characterize the process of heme leaving hemoglobin and subsequent rebinding with a NEAT domain. Our MD results highlight important amino acid residues that facilitate heme transfer and will guide further studies for the selection of best NEAT candidate to attenuate free hemoglobin toxicity.