Biomedical subjects

Eran Eyal

Publications and source records attributed to Eran Eyal.

6 recordsLinked to original sources

PubMed2007

RUN-CBFbeta interaction in C. elegans: computational prediction and experimental verification.

The Runt domain proteins are eukaryotic transcription factors that regulate major developmental pathways. All members of this family contain a highly-conserved sequence-specific DNA binding domain: the Runt domain (RD). Structural and biochemical studies have shown that the Runt domain undergoes a conformational transition upon binding to DNA and that this process is regulated by an unrelated partner protein CBFbeta that enhances the DNA binding affinity of RD. Most of the reported studies on the Runt domain transcription factors were performed on proteins from mammals and Drosophila whereas very little has been known about the C. elegans RD protein, RUN, which provides the simplest model system for understanding the function of this class of transcription factors. We performed computational studies on RD domains from various species including C. elegans, Drosophila, and human, using the atom-atom contact surface area scoring method. The scoring analysis indicates that the DNA binding regulation of the C. elegans RD protein (CeRD) occurs via its interaction with a CBFbeta-like partner, as found for the human proteins, whereas a different mode of regulation may occur in the Drosophila system. Sequence, secondary structure and fold analyses of a putative CBFbeta protein identified in the C. elegans genome, CeCBFbeta, sharing a 22% identity with the human protein, predict a similar structure of this protein to that of the human CBFbeta protein. We produced the C. elegans proteins CeRD and CeCBFbeta in bacteria and confirmed their physical interaction as well as cross interactions with the corresponding human proteins. We also confirmed the structural similarity of CBFbeta and CeCBFbeta by circular dichroism analysis. The combined results suggest that a similar mechanism of regulation operates for the human and the C. elegans RD proteins despite the low sequence identity between their CBFbeta proteins and the evolutionary distance between the two systems.

Amino Acid Sequence↗

PubMed2006

Anisotropic network model: systematic evaluation and a new web interface.

MOTIVATION: The Anisotropic Network Model (ANM) is a simple yet powerful model for normal mode analysis of proteins. Despite its broad use for exploring biomolecular collective motions, ANM has not been systematically evaluated to date. A lack of a convenient interface has been an additional obstacle for easy usage. RESULTS: ANM has been evaluated on a large set of proteins to establish the optimal model parameters that achieve the highest correlation with experimental data and its limits of accuracy and applicability. Residue fluctuations in globular proteins are shown to be more accurately predicted than those in nonglobular proteins, and core residues are more accurately described than solvent-exposed ones. Significant improvement in agreement with experiments is observed with increase in the resolution of the examined structure. A new server for ANM calculations is presented, which offers flexible options for controlling model parameters and output formats, interactive animation of collective modes and advanced graphical features. AVAILABILITY: ANM server (http://www.ccbb.pitt.edu/anm)

Algorithms↗

PubMed2005

The limit of accuracy of protein modeling: influence of crystal packing on protein structure.

The size of the protein database (PDB) makes it now feasible to arrive at statistical conclusions regarding structural effects of crystal packing. These effects are relevant for setting upper practical limits of accuracy on protein modeling. Proteins whose crystals have more than one molecule in the asymmetric unit or whose structures were determined at least twice by X-ray crystallography were paired and their differences analyzed. We demonstrate a clear influence of crystal environment on protein structure, including backbone conformations, hinge-like motions and side-chain conformations. The positions of surface water molecules tend to be variable in different crystal environments while those of ligands are not. Structures determined by independent groups vary more than structures determined by the same authors. The use of different refinement methods is a major source for this effect. Our pair-wise analysis derives a practical limit to the accuracy of protein modeling. For different crystal forms, the limit of accuracy (C(alpha), root-mean-square deviation (RMSD)) is approximately 0.8A for the entire protein, which includes approximately 0.3A due to crystal packing. For organized secondary elements, the upper limit of C(alpha) RMSD is 0.5-0.6A while for loops or protein surface it reaches 1.0A. Twenty percent of exposed side- chains exhibit different chi(1+2) conformations with approximately half of the effect also resulting from crystal packing. A web based tool for analysis and graphic presentation of surface areas of crystal contacts is available (http://ligin.weizmann.ac.il/cryco).

Computational Biology↗

PubMed2005

SPACE: a suite of tools for protein structure prediction and analysis based on complementarity and environment.

We describe a suite of SPACE tools for analysis and prediction of structures of biomolecules and their complexes. LPC/CSU software provides a common definition of inter-atomic contacts and complementarity of contacting surfaces to analyze protein structure and complexes. In the current version of LPC/CSU, analyses of water molecules and nucleic acids have been added, together with improved and expanded visualization options using Chime or Java based Jmol. The SPACE suite includes servers and programs for: structural analysis of point mutations (MutaProt); side chain modeling based on surface complementarity (SCCOMP); building a crystal environment and analysis of crystal contacts (CryCo); construction and analysis of protein contact maps (CMA) and molecular docking software (LIGIN). The SPACE suite is accessed at http://ligin.weizmann.ac.il/space.

Amino Acids↗

PubMed2004

Importance of solvent accessibility and contact surfaces in modeling side-chain conformations in proteins.

Contact surface area and chemical properties of atoms are used to concurrently predict conformations of multiple amino acid side chains on a fixed protein backbone. The combination of surface complementarity and solvent-accessible surface accounts for van der Waals forces and solvation free energy. The scoring function is particularly suitable for modeling partially buried side chains. Both iterative and stochastic searching approaches are used. Our programs (Sccomp-I and Sccomp-S), with relatively fast execution times, correctly predict chi1 angles for 92-93% of buried residues and 82-84% for all residues, with an RMSD of approximately 1.7 A for side chain heavy atoms. We find that the differential between the atomic solvation parameters and the contact surface parameters (including those between noncomplementary atoms) is positive; i.e., most protein atoms prefer surface contact with other protein atoms rather than with the solvent. This might correspond to the driving force for maximizing packing of the protein. The influence of the crystal packing, completeness of rotamer library and precise positioning of Cbeta atoms on the accuracy of side-chain prediction are examined. The Sccomp-S and Sccomp-I programs can be accessed through the Web (http://sgedg.weizmann.ac.il/sccomp.html) and are available for several platforms.

Algorithms↗

PubMed2003

Protein side-chain rearrangement in regions of point mutations.

A major problem in predicting amino acid side-chain rearrangements following point mutations is the potentially large search space. We analyzed a nonredundant data set of 393 Protein Data Bank protein pairs, each consisting of structures differing in one amino acid, to determine the number of residues changing conformation in the region of mutation. In 91-95% of cases, two or fewer residues underwent side-chain conformational change. If mutation sites with backbone displacements were excluded, the number increased to 97%. The majority of rearrangements (over 60%) were due to the inherent flexibility of side-chains, as derived from analysis of a control set of protein subunits whose crystal structures were determined more than once. Different amino acids demonstrated different degrees of flexibility near mutation sites. Large polar or charged residues, and serine, are more flexible, while the aromatic amino acids, and cysteine, are less so. This pattern is common to the inherent side-chain flexibility, as well as the increased flexibility at ligand binding sites and mutation sites. The probability for conformational change was correlated with B-factor, frequency of the side-chain conformation in proteins and solvent accessibility. The last trend was stronger for aromatic and hydrophilic residues than for hydrophobic ones. We conclude that the search space for predicting side-chain conformations in the region of mutation can be effectively restricted. However, the overall ability to predict a particular side-chain conformation, or to check predictions according to individual existing structures, is limited. These findings may be useful in deriving empirical rules for modeling side-chain conformations.

Binding Sites↗