Larisa Adamian Research Assistant Professor larisa@uic.edu Bioengineering Bioinformatics M/C 563 835 S. Wolcott Chicago, IL 60612-7340 Phone: 312.996.5624 Fax:     312.413.2018
Research Interests
Membrane proteins Structural computational biology Bioinformatics
Research Projects
Classification of Protein Functional Pockets The aim of this project is to develop a classification system of the protein functional pockets. Precomputed pockets and voids of each protein structure in the PDB databank are available from the database of Computed Atlas of Surface Topography of Proteins CASTp. Furthermore, A. Binkowski et al (JMB, 2003)have developed pvSOAR method that allows identification and assessment of statistically significant matches between pockets in CASTp database. Each pvSOAR pattern of functionally important pocket contains information about composition and spatial positioning of amino acid residues characteristic for the particular function, which should allow grouping of the similar pockets independently on the protein structure from which it has been initially derived. Such groups of similar pockets can be further linked to existing biological or biochemical knowledge and hierarchy between them being established. In this study, we explore approaches for the development of automated Functional Pocket Classification (FPC) by analyzing results of grouping of the active site pockets from zinc metalloproteases. Prediction of Buried Helices in Multispan Membrane Proteins Analysis of a database of structures of membrane proteins shows that membrane proteins composed of 10 or more transmembrane (TM) helices often contain buried helices that are inaccessible to phospholipids. We have developed a method for identifying TM helices that are least phospholipid accessible, and for prediction of fully buried TM helices in membrane proteins from sequence information alone. Our method is based on the calculation of residue lipophilicity and evolutionary conservation. Given that the number of buried helices in a membrane protein is known, our method achieves Matthew.s correlation coefficient of 0.68. To rank helices in your membrane protein by solvent accessibility, click here. Prediction of Lipid Exposed Surfaces in Multispan Membrane Proteins In this project, we develop a method for prediction of the TM helix orientation, which is an essential step in ab initio modeling of membrane proteins. Our method is based on a canonical model of the heptad repeat originally developed for coiled coils. We identify the surface patches that interface with lipid molecules at an accuracy of about 90% from the sequence information alone, using an empirical scoring function LIPS (LIPid-facing Surface), which is based on lipophilicity and conservation of residues in the helix. To predict lipid-facing surfaces in TM helices of your membrane protein, click here. Empirical Lipid Propensities of Amino Acid Residues in Multispan Membrane Proteins In this project, we analyze lipid-accessible surfaces of polytopic membrane proteins and develop TMLIP (TransMembrane helix - LIPid), an empirically derived propensity of individual residue types to face phospholipid membrane. Updated propensities are available here. Higher Order Interhelical Interactions in Membrane Proteins In this project, we use Delaunay triangulation and alpha shape to identify regions with three-atom overlaps from three different residues residing on at least two TM helices. The observed frequences of interhelical triple clusters are compared to the expected random frequences. We assess the confidence intervals for each of the 1540 possible triples using studentized nested bootstrap method on 5000x100 resampled data. We determined 12 high propensity triple clusters at 95% confidence level. The library of interacting interhelical triplets is available here. Helix-Helix Packing and Interfacial Pairwise Interactions of Residues in Membrane Proteins Helix-helix packing plays a critical role in maintaining the tertiary structures of helical membrane proteins. We developed a new computational method to characterize the nearest neighboring atoms that are in physical contact. This allowed us to determine the coordination number for non-bonded interactions for each of the residue types and to estimate the membrane helical interfacial pairwise (MHIP) propensity. Updated MHIP propensities are available here. Interhelical Hydrogen Bonds and Spatial Motifs in Membrane Proteins Polar and ionizable amino acid residues are frequently found in the transmembrane (TM) regions of membrane protein. In this study, we show that they help to form extensive hydrogen bond connections between TM helices. We find that almost all TM helices have interhelical hydrogen bonding. In addition, we find that a pair of contacting TM helices is packed much tighter when there are interhelical hydrogen bonds between them. We describe new spatial motifs in TM helices: "Polar clamp" and "serine zipper". Protein Functions from Matching Spatial Surface Patterns Proteins carry out thier functions by interacting with other molecules, but the functional surfaces often involve only a small number of key residues. These residues are dispersed in diverse regions of the primary sequences and are difficult to detect by sequences - based methods alone. Identifying spatial motifs of proteins that are functionally relevant is therefore an important task of structural bioinformatics. We have identified and characterized exhaustively 910,379 surface pockets and interior voids on 12,177 protein structures from the PDB databank. These pockets are available from CASTp database. The approach is based on weighted Delaunay triangulation and alpha shape. We analyze the patterns of sequence-order dependent residues on protein surface pockets. After concatenating residues located in the same surface pocket from primary sequences, we find that very short concatenated sequences of key residues derived automatically are often discriminating in identifying proteins with related functions. The statistical significance of pocket sequence similarity is empirically modeled using parameters estimated from random pocket sequences. We show that the model fits the extreme value distribution and validate it using the Kolmogorov-Smirnov goodness of fit test. We find that these short patterns can be used to identify related functions from proteins of the same sequence family, from proteins of low sequence identities, but of the same fold and from proteins of different folds. Any pocket from CASTp database can be searched against other pockets using pvSOAR method.
Publications
Adamian L & Liang J. "Prediction of helix orientation in polytopic membrane proteins." BMC Structural Biology (submitted) Adamian L & Liang J. "Prediction of buried helices in multispan alpha helical membrane proteins." Proteins 2006; 63:1-5 Liang J, Adamian L, Jackups RJ. "The membrane-water interface region of membrane proteins: structural bias and the anti-snorkeling effect." Trends Biochem Sci 2005; 30:355-357. Adamian L, Vikas N, DeGrado W & Liang J. "Empirical lipid potentials of amino acid residues in multispan alpha helical membrane proteins." Proteins 2005; 59:496-509 Binkowski TA, Adamian L & Liang J. "Inferring functional relationships of proteins from local sequence and spatial surface patterns." J Mol Biol 2003; 332:505-526 Lear JD, Gratkowski H, Adamian L, Liang J, DeGrado WF. "Position-dependence of stabilizing polar interactions of asparagine in transmembrane helical bundles." Biochemistry 2003; 42:6400-6407 Adamian L, Jackups RJ, Binkowski TA & Liang J. "Higher-order interhelical spatial interactions in membrane proteins." J Mol Biol 2003; 327:251-272 Adamian L & Liang J. "Interhelical hydrogen bonds and spatial motifs in membrane proteins: polar clamps and serine zippers." Proteins 2002; 47:209-218 Oezguen N, Adamian L, Xu Y, Rajarathnam K & Braun W. "Automated assignment and 3D structure calculations using combinations of 2D homonuclear and 3D heteronuclear NOESY spectra". J Biomolecular NMR 2002; 22:249-263 Adamian L & Liang J. "Helix-helix packing and interfacial pairwise interactions of residues in membrane proteins." J Mol Biol 2001; 311:891-907 Kosynkina (Adamian) L, Wang W & Liang TC. "A convenient synthesis of chiral peptide nucleic acid (PNA) monomers." Tetrahedron Letters 1994; 35:5173-5176
Favorite Links
Membrane proteins of known structure from Stephen White Laboratory at UC Irvine