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Molecular simulation of structures, dynamics and interactions with ATP of P-type ATPases nucleotide-binding domains.

To understand molecular mechanisms of enzymes analysis of their spatial structures is needed. However spatial structures of many important enzymes (firstly, most of membrane-bound proteins) remains unknown due to experimental problems. So, in these cases very helpful may be building of proteins 3D-models on the basis of sequences homology with proteins, which spatial structures are determined experimentally. Future study of 3D-models using molecular simulation methods allows to effectively analyzing experimental data (such as data of site-directed mutagenesis) and to proposing new hypothesis about protein’s functioning.

P-type ATPases are important and large class of enzymes which transporting special cations across membrane and produce their concentration gradient using the energy of ATP hydrolysis. Spatial structures of atomic resolution were determined (since 2000) only for one member of this class — Ca-ATPase of sarcoplasmic reticulum. On the basis of structures of Ca-ATPase we build 3D-models of nucleotide binding domains of two other class member — Na,K-ATPase and copper-transporting ATPase (or WilsoN Disease Protein, WNDP). Next we performed MD study and ATP docking simulation for these 3D-models. Analysis of molecular simulations results and experimental data allows us to better understand mechanism of interaction of P-type ATPases with ATP and to give new interpretations of site directed mutagenesis data.

Fig. 1. Spatial structures of P-type ATPases nucleotide-binding domain: A. Ca-ATPase X—ray structure and B. WNDP 3D-model building on the basis of structure of Ca-ATPase. Several residues important for ATP binding and catalysis are shown.

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