31 research outputs found
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
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
Structure fluctuations and conformational changes in protein binding
Structure fluctuations and conformational changes accompany all biological
processes involving macromolecules. The paper presents a classification of
protein residues based on the normalized equilibrium fluctuations of the
residue centers of mass in proteins and a statistical analysis of conformation
changes in the side-chains upon binding. Normal mode analysis and an elastic
network model were applied to a set of protein complexes to calculate the
residue fluctuations and develop the residue classification. Comparison with a
classification based on normalized B-factors suggests that the B-factors may
underestimate protein flexibility in solvent. Our classification shows that
protein loops and disordered fragments are enriched with highly fluctuating
residues and depleted with weakly fluctuating residues. To calculate the
dihedral angles distribution functions, the configuration space was divided
into cells by a cubic grid. The effect of protein association on the
distribution functions depends on the amino acid type and a grid step in the
dihedral angles space. The changes in the dihedral angles increase from the
near-backbone dihedral angle to the most distant one, for most residues. On
average, one fifth of the interface residues change the rotamer state upon
binding, whereas the rest of the interface residues undergo local readjustments
within the same rotamer.Comment: 13 pages, 6 figure
Structure Fluctuations and Conformational Changes in Protein Binding
Structure fluctuations and conformational changes accompany all biological processes involving macromolecules. The paper presents a classification of protein residues based on the normalized equilibrium fluctuations of the residue centers of mass in proteins and a statistical analysis of conformation changes in the side-chains upon binding. Normal mode analysis and an elastic network model were applied to a set of protein complexes to calculate the residue fluctuations and develop the residue classification. Comparison with a classification based on normalized B-factors suggests that the B-factors may underestimate protein flexibility in solvent. Our classification shows that protein loops and disordered fragments are enriched with highly fluctuating residues and depleted with weakly fluctuating residues. Strategies for engineering thermostable proteins are discussed. To calculate the dihedral angles distribution functions, the configuration space was divided into cells by a cubic grid. The effect of protein association on the distribution functions depends on the amino acid type and a grid step in the dihedral angles space. The changes in the dihedral angles increase from the near-backbone dihedral angle to the most distant one, for most residues. On average, one fifth of the interface residues change the rotamer state upon binding, whereas the rest of the interface residues undergo local readjustments within the same rotamer
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
Rotamer libraries and probabilities of transition between rotamers for the side chains in protein-protein binding
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Simulated unbound structures for benchmarking of protein docking in the dockground resource
Background
Proteins play an important role in biological processes in living organisms. Many protein functions are based on interaction with other proteins. The structural information is important for adequate description of these interactions. Sets of protein structures determined in both bound and unbound states are essential for benchmarking of the docking procedures. However, the number of such proteins in PDB is relatively small. A radical expansion of such sets is possible if the unbound structures are computationally simulated.
Results
The dockground public resource provides data to improve our understanding of protein–protein interactions and to assist in the development of better tools for structural modeling of protein complexes, such as docking algorithms and scoring functions. A large set of simulated unbound protein structures was generated from the bound structures. The modeling protocol was based on 1 ns Langevin dynamics simulation. The simulated structures were validated on the ensemble of experimentally determined unbound and bound structures. The set is intended for large scale benchmarking of docking algorithms and scoring functions.
Conclusions
A radical expansion of the unbound protein docking benchmark set was achieved by simulating the unbound structures. The simulated unbound structures were selected according to criteria from systematic comparison of experimentally determined bound and unbound structures. The set is publicly available at http://dockground.compbio.ku.edu
Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors
The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures –8 determined here– of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene-restricted ontogenies