Sequence composition and environment effects on residue fluctuations in protein structures

The spectrum and scale of fluctuations in protein structures affect the range of cell phenomena, including stability of protein structures or their fragments, allosteric transitions and energy transfer. The study presents a statistical-thermodynamic analysis of relationship between the sequence composition and the distribution of residue fluctuations in protein-protein complexes. A one-node-per residue elastic network model accounting for the nonhomogeneous protein mass distribution and the inter-atomic interactions through the renormalized inter-residue potential is developed. Two factors, a protein mass distribution and a residue environment, were found to determine the scale of residue fluctuations. Surface residues undergo larger fluctuations than core residues, showing agreement with experimental observations. Ranking residues over the normalized scale of fluctuations yields a distinct classification of amino acids into three groups. The structural instability in proteins possibly relates to the high content of the highly fluctuating residues and a deficiency of the weakly fluctuating residues in irregular secondary structure elements (loops), chameleon sequences and disordered proteins. Strong correlation between residue fluctuations and the sequence composition of protein loops supports this hypothesis. Comparing fluctuations of binding site residues (interface residues) with other surface residues shows that, on average, the interface is more rigid than the rest of the protein surface and Gly, Ala, Ser, Cys, Leu and Trp have a propensity to form more stable docking patches on the interface. The findings have broad implications for understanding mechanisms of protein association and stability of protein structures.Comment: 8 pages, 4 figure

Chasing Funnels on Protein-Protein Energy Landscapes at Different Resolutions

This is the published version, also available here: http://dx.doi.org/10.1529/biophysj.108.132977.Studies of intermolecular energy landscapes are important for understanding protein association and adequate modeling of protein interactions. Landscape representation at different resolutions can be used for the refinement of docking predictions and detection of macro characteristics, like the binding funnel. A representative set of protein-protein complexes was used to systematically map the intermolecular landscape by grid-based docking. The change of the resolution was achieved by varying the range of the potential, according to the variable resolution GRAMM methodology. A formalism was developed to consistently parameterize the potential and describe essential characteristics of the landscape. The results of gradual landscape smoothing, from high to low resolution, indicate that i), the number of energy basins, the landscape ruggedness, and the slope decrease accordingly; ii), the number of near-native matches, defined as those inside the funnel, increases until the trend breaks down at critical resolution; the rate of the increase and the critical resolution are specific to the type of a complex (enzyme inhibitor, antigen-antibody, and other), reflect known underlying recognition factors, and correlate with earlier determined estimates of the funnel size; iii), the native/nonnative energy gap, a major characteristic of the energy minima hierarchy, remains constant; and iv), the putative funnel (defined as the deepest basin) has the largest average depth-related ruggedness and slope, at all resolutions. The results facilitate better understanding of the binding landscapes and suggest directions for implementation in practical docking protocols

Side-chain conformational changes upon protein-protein association

Conformational changes upon protein-protein association are the key element of the binding mechanism. The study presents a systematic large-scale analysis of such conformational changes in the side chains. The results indicate that short and long side chains have different propensities for the conformational changes. Long side chains with three or more dihedral angles are often subject to large conformational transition. Shorter residues with one or two dihedral angles typically undergo local conformational changes not leading to a conformational transition. The relationship between the local readjustments and the equilibrium fluctuations of a side chain around its unbound conformation is suggested. Most of the side chains undergo larger changes in the dihedral angle most distant from the backbone. The amino acids with symmetric aromatic (Phe and Tyr) and charged (Asp and Glu) groups show the opposite trend where the near-backbone dihedral angles change the most. The frequencies of the core-to-surface interface transitions of six nonpolar residues and Tyr exceed the frequencies of the opposite, surface-to-core transitions. The binding increases both polar and nonpolar interface areas. However, the increase of the nonpolar area is larger for all considered classes of protein complexes. The results suggest that the protein association perturbs the unbound interfaces to increase the hydrophobic forces. The results facilitate better understanding of the conformational changes in proteins and suggest directions for efficient conformational sampling in docking protocols.Comment: 21 pages, 6 figure

Local packing modulates diversity of iron pathways and cooperative behavior in eukaryotic and prokaryotic ferritins

Ferritin-like molecules show a remarkable combination of the evolutionary conserved activity of iron uptake and release that engage different pores in the conserved ferritin shell. It was hypothesized that pore selection and iron traffic depend on dynamic allostery with no conformational changes in the backbone. In this study, we detect the allosteric networks in Pseudomonas aeruginosa bacterioferritin (BfrB), bacterial ferritin (FtnA), and bullfrog M and L ferritins (Ftns) by a network-weaving algorithm (NWA) that passes threads of an allosteric network through highly correlated residues using hierarchical clustering. The residue-residue correlations are calculated in the packing-on elastic network model that introduces atom packing into the common packing-off model. Applying NWA revealed that each of the molecules has an extended allosteric network mostly buried inside the ferritin shell. The structure of the networks is consistent with experimental observations of iron transport: The allosteric networks in BfrB and FtnA connect the ferroxidase center with the 4-fold pores and B-pores, leaving the 3-fold pores unengaged. In contrast, the allosteric network directly links the 3-fold pores with the 4-fold pores in M and L Ftns. The majority of the network residues are either on the inner surface or buried inside the subunit fold or at the subunit interfaces. We hypothesize that the ferritin structures evolved in a way to limit the influence of functionally unrelated events in the cytoplasm on the allosteric network to maintain stability of the translocation mechanisms. We showed that the residue-residue correlations and the resultant long-range cooperativity depend on the ferritin shell packing, which, in turn, depends on protein sequence composition. Switching from the packing-on to the packing-off model reduces correlations by 35%-38% so that no allosteric network can be found. The influence of the side-chain packing on the allosteric networks explains the diversity in mechanisms of iron traffic suggested by experimental approaches. © 2014 AIP Publishing LLC

Rotamer libraries and probabilities of transition between rotamers for the side chains in protein-protein binding

Author's Pre-print: green tick author can archive pre-print (ie pre-refereeing) Author's Post-print: grey tick subject to Restrictions below, author can archive post-print (ie final draft post-refereeing) Restrictions: 12 months embargo Publisher's Version/PDF: cross author cannot archive publisher's version/PDF General Conditions: Some journals have separate policies, please check with each journal directly On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network Author's pre-print may not be updated with Publisher's Version/PDF Author's pre-print must acknowledge acceptance for publication Non-Commercial Publisher's version/PDF cannot be used Publisher source must be acknowledged with citation Must link to publisher version with set statement (see policy) If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 month

Correlation analysis of the side-chains conformational distribution in bound and unbound proteins

Background: Protein interactions play a key role in life processes. Characterization of conformational properties of protein-protein interactions is important for understanding the mechanisms of protein association. The rapidly increasing amount of experimentally determined structures of proteins and protein-protein complexes provides foundation for research on protein interactions and complex formation. The knowledge of the conformations of the surface side chains is essential for modeling of protein complexes. The purpose of this study was to analyze and compare dihedral angle distribution functions of the side chains at the interface and non-interface areas in bound and unbound proteins. Results: To calculate the dihedral angle distribution functions, the configuration space was divided into grid cells. Statistical analysis showed that the similarity between bound and unbound interface and non-interface surface depends on the amino acid type and the grid resolution. The correlation coefficients between the distribution functions increased with the grid spacing increase for all amino acid types. The Manhattan distance showing the degree of dissimilarity between the distribution functions decreased accordingly. Short residues with one or two dihedral angles had higher correlations and smaller Manhattan distances than the longer residues. Met and Arg had the slowest growth of the correlation coefficient with the grid spacing increase. The correlations between the interface and non-interface distribution functions had a similar dependence on the grid resolution in both bound and unbound states. The interface and non-interface differences between bound and unbound distribution functions, caused by biological protein-protein interactions or crystal contacts, disappeared at the 70° grid spacing for interfaces and 30° for non-interface surface, which agrees with an average span of the side-chain rotamers. Conclusions: The two-fold difference in the critical grid spacing indicates larger conformational changes upon binding at the interface than at the rest of the surface. At the same time, transitions between rotamers induced by interactions across the interface or the crystal packing are rare, with most side chains having local readjustments that do not change the rotameric state. The analysis is important for better understanding of protein interactions and development of flexible docking approaches. Keywords: Protein interactions; Protein docking; Molecular recognition; Conformational analysi

Side-Chain Conformational Changes upon Protein-Protein Association

Conformational changes upon protein-protein association are the key element of the binding mechanism. The study presents a systematic large-scale analysis of such conformational changes in the side chains. The results indicate that short and long side chains have different propensities for the conformational changes. Long side chains with three or more dihedral angles are often subject to large conformational transition. Shorter residues with one or two dihedral angles typically undergo local conformational changes not leading to a conformational transition. The relationship between the local readjustments and the equilibrium fluctuations of a side chain around its unbound conformation is suggested. Most of the side chains undergo larger changes in the dihedral angle most distant from the backbone. The frequencies of the core-to-surface interface transitions of six nonpolar residues and Tyr are larger than the frequencies of the opposite, surface-to-core transitions. The binding increases both polar and nonpolar interface areas. However, the increase of the nonpolar area is larger for all considered classes of protein complexes, suggesting that the protein association perturbs the unbound interfaces to increase the hydrophobic contribution to the binding free energy. To test modeling approaches to side-chain flexibility in protein docking, conformational changes in the X-ray set were compared with those in the docking decoys sets. The results lead to a better understanding of the conformational changes in proteins and suggest directions for efficient conformational sampling in docking protocols