A novel method for packing quality assessment of transmembrane α-helical domains in proteins (original) (raw)

Integral membrane proteins (MPs) are of exception al biological importance; they are known to mediate transmembrane (TM) signal transduction, light absorp tion, generation of TM potential, etc. For example, G protein coupled receptors (GPCR), the broadest and most important class of MPs, are targets for more than 50% of all currently marketed drugs [1] since their malfunction is connected to a number of diseases . The functioning of MPs depends primarily on the TM domain, which often binds a ligand and accommodates conformational reorga nization initiating intracellular response. Information on the structure and functioning of TM domains is urgently required for pharmaceutical applications, such as struc ture based drug design. Modern experimental techniques of three dimensional (3D) structure determination, such as X ray crystallography and NMR spectroscopy, on the other hand, often fail to solve the problem due to techni cal difficulties related to protein purification and crystal lization . Only a few tens of MP structures have been Abstract-Here we present a novel method for assessment of packing quality for transmembrane (TM) domains of α heli cal membrane proteins (MPs), based on analysis of available high resolution experimental structures of MPs. The present ed concept of protein membrane environment classes permits quantitative description of packing characteristics in terms of membrane accessibility and polarity of the nearest protein groups. We demonstrate that the method allows identification of native like conformations among the large set of theoretical MP models. The developed "membrane scoring function" will be of use for optimization of TM domain packing in theoretical models of MPs, first of all G protein coupled receptors.