Modelling the polypeptide backbone with ‘spare parts’ from known protein structures

Abstract

An automatic procedure for building a protein polyalanine backbone from C alpha positions and 'spare parts' retrieved from a data base of 66 high-resolution protein structures is described. Protein backbones are constructed from overlapping fragments of variable length, which allows the backbone of regular secondary structure elements to be built in one block. The procedure is shown to yield backbones which compare very favourably with those from highly refined X-ray structures (r.m.s. deviation between generated and crystal structures less than 1A). The method is furthermore quite insensitive to experimental errors in C alpha positions as well as to the size of the data base, and is seen to yield valuable insight into the relationships between sequence and 3-D structure: one example on triose phosphate isomerase, a beta-barrel protein, shows that beta alpha loops can be considered as structurally more uncommon than alpha beta loops. The 'spare parts' approach is also found to be useful for general-purpose modelling of local structural changes produced by insertion or deletion of residues. It should, however, be used with caution. Crude selection criteria based solely on fragment length and geometric fit to the loop base regions yield realistic backbones in about two-thirds of the test cases (r.m.s. deviations from refined crystal structure approximately 1A). In the remaining cases, sequence information, in particular the presence of glycine residues which tend to adopt more unusual backbone conformations, must be considered to obtain comparable results.

Molecular and structural studies of Japanese patients with sialidosis type 1

“…Loop regions were then constructed by selecting a fragment for modeling loop regions from the general protein database (Jones and Thirup 1986;Claessens et al 1989). The force field for simulation of proteins (Weiner et al 1984(Weiner et al , 1986) was employed in the minimization steps to optimize the geometry of a molecule.…”

Homology modeling using simulated annealing of restrained molecular dynamics and conformational search calculations with CONGEN: Application in predicting the three‐dimensional structure of murine homeodomain Msx‐1

“…Such homology models are very useful in certain protein engineering applications that do not require an accurate high-resolution structure, and for accelerating experimental structure determinations by NMR and X-ray crystallography using molecular replacement methods. Several successful approaches for homology modeling (reviewed in Sali, 1995) have included knowledge-based interactive model building (Blundell et al, 1983;Claessens et al, 1989;Bazan, 1990;Bajorath et al, 1993), systematic conformational search (Bruccoleri & Novotny, 1992), combinatorial side-chain conformational analysis (Ponder & Richards, 1987), polypeptide segment matching (Levitt, 1992), conformational threading (Jones et al, 1992), distance geometry and/or simulated annealing calculations using homology constraints (Engh et al, 1990;Havel & Snow, 1991;Fujiyoshi-Yoneda et al, 1991;Brocklehurst & Perham, 1993, Havel, 1993Snow, 1993;Srinivasan et al, 1993;Sudarsanam et al, 1994), and structure generation by satisfaction of spatial restraints derived from sequence alignments and expressed as probability density functions (Sali & Blundell, 1993). However, there is no general agreement on what is the most reliable method for this process.…”

Modeling protein loops using a ϕi+1, Ψi dimer database

“…One must consider the flexibility of the peptide backbone, diversity in side-chain rotamers, steric constraints between atoms, and chemical connectivity constraints imposed by the topology on both sides of a loop. Many methods exist in the literature for modeling variable loops with limited success (Fine et al, 1986;Moult & James, 1986;Snow & Amzel, 1986;Bruccoleri & Karplus, 1987;Shenkin et al, 1987;Chothia et al, 1989;Claessens Martin et al, 1989;Collura et ai., 1993). This is mainly because the constraints listed above are not sufficient to make an unambiguous choice from a large ensemble of geometrically and energetically favorable conformations.…”