Structural relationships of homologous proteins as a fundamental principle in homology modeling

Abstract

Protein structure prediction is based mainly on the modeling of proteins by homology to known structures; this knowledge-based approach is the most promising method to date. Although it is used in the whole area of protein research, no general rules concerning the quality and applicability of concepts and procedures used in homology modeling have been put forward yet. Therefore, the main goal of the present work is to provide tools for the assessment of accuracy of modeling at a given level of sequence homology. A large set of known structures from different conformational and functional classes, but various degrees of homology was selected. Pairwise structure superpositions were performed. Starting with the definition of the structurally conserved regions and determination of topologically correct sequence alignments, we correlated geometrical properties with sequence homology (defined by the 250 PAM Dayhoff Matrix) and identity. It is shown that both the topological differences of the protein backbones and the relative positions of corresponding side chains diverge with decreasing sequence identity. Below 50% identity, the deviation in regions that are structurally not conserved continually increases, thus implying that with decreasing sequence identity modeling has to take into account more and more structurally diverging loop regions that are difficult to predict.

Chloroplast Glyceraldehyde-3-phosphate Dehydrogenase Contains a Single Disulfide Bond Located in the C-terminal Extension to the B Subunit

“…For models based on sequence alignment the lowest acceptable homology (sequence identity after alignment) is usually considered to be about 30% (see Ref. 16). Here, however, the high percentage of superimposable ␣ carbons in the two model enzymes and the similarities in sequence in the B subunit and Sulfolobus enzyme made it seem reasonable to use the three-dimensional structure of the archaeal C terminus to predict the positions of the two Cys residues in the C-terminal segment of the chloroplastic B subunit.…”

Predicting the structure of the light-harvesting complex II ofrhodospirillum molischianum

“…molischiunum. Presently, prediction of tertiary structure is only of practical use when the structure of a homologous protein is already known (Fasman, 1989;Hilbert et al, 1993). We illustrate how one can proceed to predict the structure of an integral membrane protein in the case that a highly homologous structure is not available.…”

A Three-dimensional Model of Human Organic Anion Transporter 1

“…Emerging methods to overcome problems with protein crystallization include the development of computational models based on ab initio techniques (building the structure amino acid by amino acid), sequence homology, or fold assignment (10). If sequence homology is low (Ͻ50%), fold recognition offers a viable alternative for model building (10,11). Threading, or fold recognition, predicts structure based upon two-dimensional fold recognition between the target (a protein of unknown structure) and the template (a protein of known structure).…”