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S Sudarsanam

Publications and source records attributed to S Sudarsanam.

8 recordsLinked to original sources
PubMed1998

Structural diversity of sequentially identical subsequences of proteins: identical octapeptides can have different conformations.

One of the most important questions in the protein folding problem is whether secondary structures are formed entirely by local interactions. One way to answer this question is to compare identical subsequences of proteins to see if they have identical structures. Such an exercise would also reveal a lower limit on the number of amino acids needed to form unique secondary structures. In this context, we have searched the April 1996 release of the Protein Data Bank for sequentially identical subsequences of proteins and compared their structures. We find that identical octamers can have different conformations. In addition, there are several examples of identical heptamers with different conformations, and the number of identical hexamers with different conformations has increased since the previous PDB releases. These observations imply that secondary structure can be formed entirely by non-local interactions and that an identical match of up to eight amino acids may not imply structural similarity. In addition to the larger context of the protein folding problem, these observations have implications for protein structure prediction methods.

Databases, Factual↗
PubMed1997

Sequence-dependent conformational sampling using a database of phi(i)+1 and psi(i) angles for predicting polypeptide backbone conformations.

A method to sample the conformational space of polypeptides in a sequence-dependent manner was developed and applied to predict backbone conformations of polypeptides. The method uses a database of phi(i)+1 and psi(i) angles sorted into pools corresponding to 400 dimers of naturally occurring amino acids. The pools of phi(i)+1 and psi(i) angles for dimers were further dynamically divided into sub-pools based on the homology of two amino acids on either side of the dimer. Typically, 10000 backbone conformations for every overlapping hexamer of a polypeptide are generated by randomly assigning a set of phi(i)+1 and psi(i) angles for every dimer from the sorted sub-pool for that dimer. The conformational preference for each hexamer is evaluated by superimposing each simulated conformation on a set of pre-selected hexameric templates which are derived from high-resolution crystal structures representing helical, extended and turn conformations. A model is classified as compatible with a template if it has a backbone root mean square deviation of < or = 1 A to that template. The template that has the highest population of compatible models for a given hexamer is interpreted as the most probable conformation of that hexamer. The method was applied to predict backbone conformations that arise primarily from local interactions and the predictions were compared with experimental results. Results from simulations on structurally characterized polypeptides in helical, extended, turn and mixed alphabeta conformations are presented to demonstrate the predictive powers of the method. It is also demonstrated how models of overlapping hexamers can be assembled to obtain near-native models for the entire sequence.

Databases, Factual↗
PubMed1995

Modeling protein loops using a phi i + 1, psi i dimer database.

We present an automated method for modeling backbones of protein loops. The method samples a database of phi i + 1 and psi i angles constructed from a nonredundant version of the Protein Data Bank (PDB). The dihedral angles phi i + 1 and psi i completely define the backbone conformation of a dimer when standard bond lengths, bond angles, and a trans planar peptide configuration are used. For the 400 possible dimers resulting from 20 natural amino acids, a list of allowed phi i + 1, psi i pairs for each dimer is created by pooling all such pairs from the loop segments of each protein in the nonredundant version of the PDB. Starting from the N-terminus of the loop sequence, conformations are generated by assigning randomly selected pairs of phi i + 1, psi i for each dimer from the respective pool using standard bond lengths, bond angles, and a trans peptide configuration. We use this database to simulate protein loops of lengths varying from 5 to 11 amino acids in five proteins of known three-dimensional structures. Typically, 10,000-50,000 models are simulated for each protein loop and are evaluated for stereochemical consistency. Depending on the length and sequence of a given loop, 50-80% of the models generated have no stereochemical strain in the backbone atoms. We demonstrate that, when simulated loops are extended to include flanking residues from homologous segments, only very few loops from an ensemble of sterically allowed conformations orient the flanking segments consistent with the protein topology. The presence of near-native backbone conformations for loops from five different proteins suggests the completeness of the dimeric database for use in modeling loops of homologous proteins. Here, we take advantage of this observation to design a method that filters near-native loop conformations from an ensemble of sterically allowed conformations. We demonstrate that our method eliminates the need for a loop-closure algorithm and hence allows for the use of topological constraints of the homologous proteins or disulfide constraints to filter near-native loop conformations.

Amino Acid Sequence↗
PubMed1994

Homology modeling of divergent proteins.

A method is presented for homology modeling of proteins bearing weak sequence identity to proteins of known tertiary structure. To accommodate non-identical amino acids in the core region, the backbone of the structurally conserved core of the model protein is allowed to deviate from that of the template protein. We have expanded FOLDER, a distance geometry-based homology modeling method, to allow for such displacements in the structurally conserved core. Models are built by rigidly constraining the interatomic distances within a structurally conserved segment and by allowing the interatomic distances between these segments to vary by a "divergence factor". We test this method by simulating models of the beta-barrel domain D1 of CD4 and a four-helix bundle protein cytochrome b562 using the crystal structures of Bence-Jones protein and cytochrome c' as templates, respectively. In both cases, previously published structure-based sequence alignments were used for simulating models. The root-mean-square (r.m.s.) deviation of the backbone atoms in the common core between the templates and models was found to be a function of the imposed divergence factor. Our results demonstrate that this r.m.s. deviation results from the relative displacements of structurally conserved segments to accommodate the amino acid replacements in the core of the model protein. To test the integrity of the simulated structures we compared them with their respective crystal structures. The r.m.s. deviation of the backbone atoms in the core regions of the simulated models and their respective crystal structures is approximately 1.4 A. The r.m.s. deviation for all the backbone atoms in the models, including those in the structurally variable regions, which are modeled de novo, is 2.4 A for CD4 and 3.2 A for cytochrome b562 when compared with their respective X-ray structures.

Animals↗
PubMed1993

An automated method for modeling proteins on known templates using distance geometry.

We present an automated method incorporated into a software package, FOLDER, to fold a protein sequence on a given three-dimensional (3D) template. Starting with the sequence alignment of a family of homologous proteins, tertiary structures are modeled using the known 3D structure of one member of the family as a template. Homologous interatomic distances from the template are used as constraints. For nonhomologous regions in the model protein, the lower and the upper bounds for the interatomic distances are imposed by steric constraints and the globular dimensions of the template, respectively. Distance geometry is used to embed an ensemble of structures consistent with these distance bounds. Structures are selected from this ensemble based on minimal distance error criteria, after a penalty function optimization step. These structures are then refined using energy optimization methods. The method is tested by simulating the alpha-chain of horse hemoglobin using the alpha-chain of human hemoglobin as the template and by comparing the generated models with the crystal structure of the alpha-chain of horse hemoglobin. We also test the packing efficiency of this method by reconstructing the atomic positions of the interior side chains beyond C beta atoms of a protein domain from a known 3D structure. In both test cases, models retain the template constraints and any additionally imposed constraints while the packing of the interior residues is optimized with no short contacts or bond deformations. To demonstrate the use of this method in simulating structures of proteins with nonhomologous disulfides, we construct a model of murine interleukin (IL)-4 using the NMR structure of human IL-4 as the template. The resulting geometry of the nonhomologous disulfide in the model structure for murine IL-4 is consistent with standard disulfide geometry.

Algorithms↗
PubMed1992

An approach to computer-aided inhibitor design: application to cathepsin L.

We have developed an approach to search for molecules that can be used as lead compounds in designing an inhibitor for a given proteolytic enzyme when the 3D structure of a homologous protein is known. This approach is based on taking the cast of the binding pocket of the protease and comparing its dimensions with that of the dimensions of small molecules. Herein the 3D structure of papain is used to model cathepsin L using the comparative modeling technique. The cast of the binding pocket is computed using the crystal structure of papain because the structures of papain and the model of cathepsin L are found to be similar at the binding site. The dimensions of the cast of the binding site of papain are used to screen for molecules from the Cambridge Structural Database (CSD) of small molecules. Twenty molecules out of the 80,000 small molecules in the CSD are found to have dimensions that are accommodated by the papain binding pocket. Visual comparison of the shapes of the cast and the 20 screened molecules resulted in identifying brevotoxin b, a toxin isolated from the 'red tide' dinoflagellate Ptycho brevis (previously classified as Gymonodium breve), as the structure that best fits the binding pocket of papain. We tested the proteolytic activity of papain and cathepsin L in the presence of brevotoxin b and found inhibition of papain and cathepsin L with Kis of 25 microM and 0.6 microM, respectively. We also compare our method with a more elaborate method in the literature, by presenting our results on the computer search for inhibitors of the HIV-1 protease.

Binding Sites↗