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PubMed1995

Forces of tertiary structural organization in globular proteins.

The tertiary structures of globular proteins have remarkable and complex symmetries. What forces cause them? We find that a very simple model reproduces some of those symmetries. Proteins are modeled as copolymers of specific sequences of hydrophobic (H) and polar (P) monomers (HP model) configured as self-avoiding flights on simple three-dimensional cubic lattices. The model has no parameters; we just seek the conformations that have the global maximum number of HH contacts for any given sequence. Finding global optima for chains in this model has not been computationally possible before for chains longer than 36-mers. We report here a procedure that can find all the globally optimal conformations, the number of which defines the degeneracy of a sequence, for chains up to 88 monomers long. It is about 37 orders of magnitude faster than previous exact methods. We find that degeneracy is an important aspect of sequence design. So far, we have found that four-helix bundles, alpha/beta-barrels, and parallel beta-helices are globally optimal conformations of polar/nonpolar sequences that have minimal degeneracy.

Amino Acid Sequence↗
PubMed1988

A simple qualitative representation of polypeptide chain folds: comparison of protein tertiary structures.

A new simple quantitative representation of three-dimensional structure of globular proteins is proposed which is useful for comparison of distantly related problems, computer sorting of large sets of conformations, and search of structurally similar domains in protein data base. The folding course of the polypeptide backbone is approximated by a set of successive vectors corresponding to the elements of regular secondary structure (e.g. alpha-helices, strands of beta-sheets) and non-regular segments. The parameters specifying the spatial organization of segments in this vector model are internal coordinates, namely, lengths of the vectors, planar and dihedral angles. Quantitative representation proposed allows to circumvent the problem of insertions/deletions and to avoid the stage of best superposition during protein comparison. An application was made to the comparison of three-dimensional structures of scorpion toxins Centruroides sculpturatus Ewing v-3, Buthus eupeus M9 and I5A, which have different chain lengths and low sequence similarity.

Models, Molecular↗
PubMed1990

An investigation of oligopeptides linking domains in protein tertiary structures and possible candidates for general gene fusion.

Fifty-one examples of oligopeptides linking protein domains were extracted from the Brookhaven database of three-dimensional protein structures. In general, the peptides displayed specific characteristics in composition, conformation, hydrogen bonding, flexibility and the like. The entire database was then searched for pentapeptides that would optimize these natural linker properties. The oligopeptides found are suggested as general candidates to link protein molecules or domains through gene fusion.

Amino Acid Sequence↗
PubMed1992

Effect of methyl substitution on protein tertiary structure.

Biological effects caused by the post-translational methylation of certain side chains in proteins has been thought to be due solely to changes in charge, steric relations or hydrophobicity at the site of the methyl group. However, there is increasing evidence that the presence of CH3 can also induce a "global" effect on the protein molecule. Some of the evidence is described in this paper.

Amines↗
PubMed1990

Incorporation of crystallographic temperature factors in the statistical analysis of protein tertiary structures.

A method to identify statistically significant differences between equivalent atoms in two closely related protein X-ray crystallographic structures is described. This method uses the linear relationship found between the logarithm of the distance between equivalent atoms and their mean temperature factor to determine, by linear regression, the expected difference and variance.

Animals↗
PubMed2006

Importance of the single amino acid potential in water for secondary and tertiary structures of proteins.

The structure of a protein molecule is considered to be primarily determined by the inter-amino-acid nonbonded interactions, such as hydrogen bonds. However, the conformational space of the polypeptide chain should be simultaneously restricted by the intrinsic conformational preferences of the individual amino acids. We present here precise single amino acid potential (SAAP) surfaces for glycine (For-Gly-NH(2)) and alanine (For-Ala-NH(2)) in water (epsilon = 78.39) and ether (epsilon = 4.335), which were calculated at the HF/6-31+G(d,p) level applying the self-consistent isodensity polarizable continuum model (SCIPCM) reaction field with geometry optimization in the corresponding solvents. The obtained Ramachandran potential surfaces in water showed distinct potential wells in the alpha- and beta-regions. The profiles were in almost perfect agreement with the Ramachandran plots of glycine and alanine residues in folded proteins, suggesting the Boltzmann distributions on the SAAP surfaces. Molecular simulations of polyalanines (For-Ala(n)-NH(2); n = 3-5) by using the SAAP force field equipped with the SCIPCM potentials revealed that the polyalanines readily form 3(10)-helical structures in water but not in vacuo. In ether (hydrophobic environments), the helical structures were relatively stable, but the most stable structure was assigned to a different one. These results indicated that the intrinsic conformational preferences of the individual amino acids (i.e., the SAAPs) in water are of significant importance not only for describing conformations of a polypeptide chain in the random coil state but also for understanding the folding to the secondary and tertiary structures.

Amino Acids↗
PubMed1999

Improved modeling of side-chains in proteins with rotamer-based methods: a flexible rotamer model.

Side-chain modeling has a widespread application in many current methods for protein tertiary structure determination, prediction, and design. Of the existing side-chain modeling methods, rotamer-based methods are the fastest and most efficient. Classically, a rotamer is conceived as a single, rigid conformation of an amino acid sidechain. Here, we present a flexible rotamer model in which a rotamer is a continuous ensemble of conformations that cluster around the classic rigid rotamer. We have developed a thermodynamically based method for calculating effective energies for the flexible rotamer. These energies have a one-to-one correspondence with the potential energies of the rigid rotamer. Therefore, the flexible rotamer model is completely general and may be used with any rotamer-based method in substitution of the rigid rotamer model. We have compared the performance of the flexible and rigid rotamer models with one side-chain modeling method in particular (the self-consistent mean field theory method) on a set of 20 high quality crystallographic protein structures. For the flexible rotamer model, we obtained average predictions of 85.8% for chi1, 76.5% for chi1+2 and 1.34 A for root-mean-square deviation (RMSD); the corresponding values for core residues were 93.0%, 87.7% and 0.70 A, respectively. These values represent improvements of 7.3% for chi1, 8.1% for chi1+2 and 0.23 A for RMSD over the predictions obtained with the rigid rotamer model under otherwise identical conditions; the corresponding improvements for core residues were 6.9%, 10.5% and 0.43 A, respectively. We found that the predictions obtained with the flexible rotamer model were also significantly better than those obtained for the same set of proteins with another state-of-the-art side-chain placement method in the literature, especially for core residues. The flexible rotamer model represents a considerable improvement over the classic rigid rotamer model. It can, therefore, be used with considerable advantage in all rotamer-based methods commonly applied to protein tertiary structure determination, prediction, and design and also in predictions of free energies in mutational studies.

Amino Acids↗
PubMed2004

Chromophore conformation and the evolution of tertiary structural changes in photoactive yellow protein.

We use time-resolved crystallography to observe the structural progression of a bacterial blue light photoreceptor throughout its photocycle. Data were collected from 10 ns to 100 ms after photoactivation of the E46Q mutant of photoactive yellow protein. Refinement of transient chromophore conformations shows that the spectroscopically distinct intermediates are formed via progressive disruption of the hydrogen bond network to the chromophore. Although structural change occurs within a few nanoseconds on and around the chromophore, it takes milliseconds for a distinct pattern of tertiary structural change to fully progress through the entire molecule, thus generating the putative signaling state. Remarkably, the coupling between the chromophore conformation and the tertiary structure of this small protein is not tight: there are leads and lags between changes in the conformation of the chromophore and the protein tertiary structure.

Bacterial Proteins↗
PubMed1998

Combined multiple sequence reduced protein model approach to predict the tertiary structure of small proteins.

By incorporating predicted secondary and tertiary restraints into ab initio folding simulations, low resolution tertiary structures of a test set of 20 nonhomologous proteins have been predicted. These proteins, which represent all secondary structural classes, contain from 37 to 100 residues. Secondary structural restraints are provided by the PHD secondary structure prediction algorithm that incorporates multiple sequence information. Predicted tertiary restraints are obtained from multiple sequence alignments via a two-step process: First, "seed" side chain contacts are identified from a correlated mutation analysis, and then, the seed contacts are "expanded" by an inverse folding algorithm. These predicted restraints are then incorporated into a lattice based, reduced protein model. Depending upon fold complexity, the resulting nativelike topologies exhibit a coordinate root-mean-square deviation, cRMSD, from native between 3.1 and 6.7 A. Overall, this study suggests that the use of restraints derived from multiple sequence alignments combined with a fold assembly algorithm is a promising approach to the prediction of the global topology of small proteins.

Algorithms↗
PubMed2004

ProteMiner-SSM: a web server for efficient analysis of similar protein tertiary substructures.

Analysis of protein-ligand interactions is a fundamental issue in drug design. As the detailed and accurate analysis of protein-ligand interactions involves calculation of binding free energy based on thermodynamics and even quantum mechanics, which is highly expensive in terms of computing time, conformational and structural analysis of proteins and ligands has been widely employed as a screening process in computer-aided drug design. In this paper, a web server called ProteMiner-SSM designed for efficient analysis of similar protein tertiary substructures is presented. In one experiment reported in this paper, the web server has been exploited to obtain some clues about a biochemical hypothesis. The main distinction in the software design of the web server is the filtering process incorporated to expedite the analysis. The filtering process extracts the residues located in the caves of the protein tertiary structure for analysis and operates with O(nlogn) time complexity, where n is the number of residues in the protein. In comparison, the alpha-hull algorithm, which is a widely used algorithm in computer graphics for identifying those instances that are on the contour of a three-dimensional object, features O(n2) time complexity. Experimental results show that the filtering process presented in this paper is able to speed up the analysis by a factor ranging from 3.15 to 9.37 times. The ProteMiner-SSM web server can be found at http://proteminer.csie.ntu.edu.tw/. There is a mirror site at http://p4.sbl.bc.sinica.edu.tw/proteminer/.

Binding Sites↗
PubMed1996

Probing the tertiary structure of proteins by limited proteolysis and mass spectrometry: the case of Minibody.

A strategy that combines limited proteolysis experiments and mass spectrometric analysis of the fragments generated has been developed to probe protease-accessible sites on the protein surface. This integrated approach has been employed to investigate the tertiary structure of the Minibody, a de novo designed 64-residue protein consisting of a beta-sheet scaffold based on the heavy-chain variable-domain structure of a mouse immunoglobulin and containing two segments corresponding to the hypervariable H1 and H2 regions. The low solubility of the protein prevented a detailed characterization by NMR and/or X-ray. Different proteases were used under strictly controlled conditions and the cleavage sites were mapped onto the anticipated Minibody model, leading to the identification of the most exposed regions. A single-residue mutant was constructed and characterized, following the same procedure, showing a slightly higher correspondence with the predicted model. This strategy can be used to effectively supplement NMR and X-ray investigations of protein tertiary structure, where these procedures cannot provide definitive data, or to verify and refine protein models.

Amino Acid Sequence↗
PubMedDate not supplied

Interresidue contacts in proteins and protein-protein interfaces and their use in characterizing the homodimeric interface.

The environment of amino acid residues in protein tertiary structures and three types of interfaces formed by protein-protein association--in complexes, homodimers, and crystal lattices of monomeric proteins--has been analyzed in terms of the propensity values of the 20 amino acid residues to be in contact with a given residue. On the basis of the similarity of the environment, twenty residues can be divided into nine classes, which may correspond to a set of reduced amino acid alphabet. There is no appreciable change in the environment in going from the tertiary structure to the interface, those participating in the crystal contacts showing the maximum deviation. Contacts between identical residues are very prominent in homodimers and crystal dimers and arise due to 2-fold related association of residues lining the axis of rotation. These two types of interfaces, representing specific and nonspecific associations, are characterized by the types of residues that partake in "self-contacts"--most notably Leu in the former and Glu in the latter. The relative preference of residues to be involved in "self-contacts" can be used to develop a scoring function to identify homodimeric proteins from crystal structures. Thirty-four percent of such residues are fully conserved among homologous proteins in the homodimer dataset, as opposed to only 20% in crystal dimers. Results point to Leu being the stickiest of all amino acid residues, hence its widespread use in motifs, such as leucine zippers.

Amino Acid Motifs↗
PubMed2006

Predicting the solvent accessibility of transmembrane residues from protein sequence.

In this study, we propose a novel method to predict the solvent accessible surface areas of transmembrane residues. For both transmembrane alpha-helix and beta-barrel residues, the correlation coefficients between the predicted and observed accessible surface areas are around 0.65. On the basis of predicted accessible surface areas, residues exposed to the lipid environment or buried inside a protein can be identified by using certain cutoff thresholds. We have extensively examined our approach based on different definitions of accessible surface areas and a variety of sets of control parameters. Given that experimentally determining the structures of membrane proteins is very difficult and membrane proteins are actually abundant in nature, our approach is useful for theoretically modeling membrane protein tertiary structures, particularly for modeling the assembly of transmembrane domains. This approach can be used to annotate the membrane proteins in proteomes to provide extra structural and functional information.

Cell Membrane↗
PubMed1995

A critical assessment of comparative molecular modeling of tertiary structures of proteins.

In spite of the tremendous increase in the rate at which protein structures are being determined, there is still an enormous gap between the numbers of known DNA-derived sequences and the numbers of three-dimensional structures. In order to shed light on the biological functions of the molecules, researchers often resort to comparative molecular modeling. Earlier work has shown that when the sequence alignment is in error, then the comparative model is guaranteed to be wrong. In addition, loops, the sites of insertions and deletions in families of homologous proteins, are exceedingly difficult to model. Thus, many of the current problems in comparative molecular modeling are minor versions of the global protein folding problem. In order to assess objectively the current state of comparative molecular modeling, 13 groups submitted blind predictions of seven different proteins of undisclosed tertiary structure. This assessment shows that where sequence identity between the target and the template structure is high (> 70%), comparative molecular modeling is highly successful. On the other hand, automated modeling techniques and sophisticated energy minimization methods fail to improve upon the starting structures when the sequence identity is low (approximately 30%). Based on these results it appears that insertions and deletions are still major problems. Successfully deducing the correct sequence alignment when the local similarity is low is still difficult. We suggest some minimal testing of submitted coordinates that should be required of authors before papers on comparative molecular modeling are accepted for publication in journals.

Amino Acid Sequence↗