Papers by Malcolm W MacArthur
Trends in Biotechnology, May 1, 1994
Acta Crystallographica Section D-biological Crystallography, May 1, 1999
Proteins, Nov 1, 1993
A study is presented of the conformational characteristics of NMR-derived protein structures in t... more A study is presented of the conformational characteristics of NMR-derived protein structures in the Protein Data Bank compared to X-ray structures. Both ensemble and energy-minimized average structures are analyzed. We have addressed the problem using the methods developed for crystal structures by examining the distribution of +, $, and x angles as indicators of global conformational irregularity. All these features in NMR structures occur to varying degrees in multiple conformational states. Some measures of local geometry are very tightly constrained by the methods used to generate the structure, e.g., proline + angles, or-helix +,$ angles, o angles, and C, chirality. The more lightly restrained torsion angles do show increased clustering as the number of overall experimental observations increases. +, $, and x1 angle conformational heterogeneity is strongly correlated with accessibility but shows additional differences which reflect the differing number of observations possible in NMR for the various side chains (e.g., many for Trp, few for Ser). In general, we find that the core is defined to a notional resolution of 2.0 to 2.3 A. Of real interest is the behavior of surface residues and in particular the side chains where multiple rotameric states in different structures can vary from 10% to 88%. Later generation structures show a much tighter definition which correlates with increasing use of J-coupling information, stereospecific assignments, and heteronuclear techniques. A suite of programs is being developed to address the special needs of NMR-derived structures which will take into account the existence of increased mobility in Solution.
Trends in Genetics, Sep 1, 2003
Protein Science, 1997
We have surveyed 393 N-termini of a-helices and 156 N-termini of 310-helices in 85 high resolutio... more We have surveyed 393 N-termini of a-helices and 156 N-termini of 310-helices in 85 high resolution, non-homologous protein crystal structures for N-cap side-chain rotamer preferences, hydrogen bonding patterns, and solvent accessibilities. We find very strong rotamer preferences that are unique to N-cap sites. The following rules are generally observed for N-capping in a-helices: Thr and Ser N-cap side chains adopt the gauche-rotamer, hydrogen bond to the N3 NH and have (1, restricted to 164 f 8". Asp and Asn N-cap side chains either adopt the gauche-rotamer and hydrogen bond to the N3 NH with (1, = 172 iz lo", or adopt the trans rotamer and hydrogen bond to both the N2 and N3 NH groups with (1, = 107 Ifr 19". With all other N-caps, the side chain is found in the gauche+ rotamer so that the side chain does not interact unfavorably with the N-terminus by blocking solvation and (1, is unrestricted. An i, i + 3 hydrogen bond from N3 NH to the N-cap backbone C = O in more likely to form at the N-terminus when an unfavorable N-cap is present. In the 310-helix Asn and Asp remain favorable N-caps as they can hydrogen bond to the N2 NH while in the trans rotamer; in contrast, Ser and Thr are disfavored as their preferred hydrogen bonding partner (N3 NH) is inaccessible. This suggests that Ser is the optimum choice of N-cap when a-helix formation is to be encouraged while 310-helix formation discouraged. The strong energetic and structural preferences found for N-caps, which differ greatly from positions within helix interiors, suggest that N-caps should be treated explicitly in any consideration of helical structure in peptides or proteins.
Current Opinion in Structural Biology, Oct 1, 1998
The growing number of protein structures solved at atomic resolution holds the promise of further... more The growing number of protein structures solved at atomic resolution holds the promise of further improvements in geometry-based validation parameters. Additionally, the estimated standard uncertainties of the atomic coordinates have been computed for a number of X-ray structures, providing a measure of the coordinate precision. In NMR spectroscopy, a measure analogous to the crystallographic R-factor has been developed.
Journal of Molecular Biology, Mar 1, 1991
To study the influence of proline residues on three-dimensional structure, an analysis has been m... more To study the influence of proline residues on three-dimensional structure, an analysis has been made of all proline residues and their local conformations extracted from the Brookhaven Protein Data bank. We have considered the conformation of the proline itself, the relative occurrence of cis and trans peptides preceding proline residues, the influence of proline on the conformation of the preceding residue and the conformations of various proline patterns (Pro-Pro, Pro-X-Pro, etc.). The results highlight the unique role of proline in determining local conformation.
Stereochemical quality of protein structure coordinates
Proteins, Apr 1, 1992
Methods have been developed to assess the stereochemical quality of any protein structure both gl... more Methods have been developed to assess the stereochemical quality of any protein structure both globally and locally using various criteria. Several parameters can be derived from the coordinates of a given structure. Global parameters include the distribution of phi, psi and chi 1 torsion angles, and hydrogen bond energies. There are clear correlations between these parameters and resolution; as the resolution improves, the distribution of the parameters becomes more clustered. These features show a broad distribution about ideal values derived from high-resolution structures. Some structures have tightly clustered distributions even at relatively low resolutions, while others show abnormal scatter though the data go to high resolution. Additional indicators of local irregularity include proline phi angles, peptide bond planarities, disulfide bond lengths, and their chi 3 torsion angles. These stereochemical parameters have been used to generate measures of stereochemical quality which provide a simple guide as to the reliability of a structure, in addition to the most important measures, resolution and R-factor. The parameters used in this evaluation are not novel, and are easily calculated from structure coordinates. A program suite is currently being developed which will quickly check a given structure, highlighting unusual stereochemistry and possible errors.
PROCHECK: a program to check the stereochemical quality of protein structures
Journal of Applied Crystallography, Apr 1, 1993
The PROCHECK suite of programs provides a detailed check on the stereochemistry of a protein stru... more The PROCHECK suite of programs provides a detailed check on the stereochemistry of a protein structure. Its outputs comprise a number of plots in PostScript format and a comprehensive residue-by-residue listing. These give an assessment of the overall quality of the structure ...
Acta Crystallographica Section A, Aug 8, 1996
Current Opinion in Structural Biology, Oct 1, 1994
Over the past few years, several protein structures solved by X-ray crystallography have been fou... more Over the past few years, several protein structures solved by X-ray crystallography have been found to contain serious errors. This has prompted the development of methods for validating protein structures, in both the X-ray and NMR fields. A number of computational tools have recently been developed for assessing structures independently of the experimental data, thereby providing an additional, complementary check on their correctness. In effect, the tests assess the normality of a protein and are both local, checking the correctness of the local geometry, and global, verifying the overall fold. In structure determination by NMR the problems of validation are compounded by multiple solutions for the experimental data and lack of agreement over means of assessing the fit of the models to the data.
Assessment of comparative modeling in CASP2
Proteins, 1997
An assessment is presented for all submissions to the comparative modeling challenge in the 1996 ... more An assessment is presented for all submissions to the comparative modeling challenge in the 1996 Critical Assessment of Structure Prediction (CASP2). Of the original 12 target structures, 9 were solved prior to the meeting: 8 by X-ray crystallography and 1 by NMR spectroscopy. These targets varied over a large range of difficulty, as assessed by the percentage sequence identity with the principal parent structure, which ranged from 20% up to 85%. The overall quality of the models reflected the similarity of the principal parent. As expected, when the sequence alignment was correct, the core was accurately modeled, with the largest deviations occurring in the loops. Models were built which gave C alpha root-mean-square deviations (RMSDs) compared with the observed structure of < 1 A for targets with high parental similarity; even at 26% sequence identity, the best model structures had C alpha deviations of only 2.2 A. Overall, these deviations are comparable with those observed between the parent structure and the target, but locally there are several examples where the model approaches closer to the target than does the parent. There were three targets below 25% sequence identity, and the models generated for these targets were, in general, significantly less accurate. This principally reflects errors in the alignment which, if systematically shifted, can generate C alpha RMSDs > 18 A. Compared with CASP1, the geometry of the models was significantly improved with no D-amino acids. By far the major contribution to RMSD error was the alignment accuracy, which varied from 100% down to 7% over the range of targets. In the structurally variable regions, global shifts, caused by hinge bending, were the major source of error, giving significantly lower local RMSDs than global RMSDs. In over 50% of these noncore regions, the difference between global and local RMSDs was more than 3 A, and was as high as 10 A for one structurally variable region. For the side chains, the chi 1 RMSDs are strongly correlated with the C alpha RMSDs. For models with C alpha deviations less than 1 A, on average 78.5% of side chains are placed in the correct rotamer, although the chi 1 RMSDs, though clearly better than random, were disappointing at around 46 degrees. As the backbone deviations increased, the side chain placement became less accurate, with an average chi 1 RMSD of 75 degrees on a 1.5-2.5 A C alpha backbone (average 51.4% correct rotamer). Refinement by energy minimization or molecular dynamics made only minor adjustments to improve local geometry and generally made small, but not significant, improvements to the RMSD. In total, 19 groups submitted 62 models (89 coordinate sets) that could be assessed. Most modelers used manual adjustments to sequence alignments and, in general, good alignments were obtained down to 25% sequence identity. The modeling methods ranged from "classical" modeling, involving core building followed by loop and side chain addition, to more sophisticated approaches based on probability distributions, Monte Carlo sampling or distance geometry. For each target, several groups produced equally good models, given the expected errors in the structures (about 0.5 A). No one method came out as clearly superior, although the approaches that inherit directly from the parents generally performed better than the more radical techniques. However, for each target there were some poor models, usually reflecting a poor sequence alignment, and the range of accuracy for each target is therefore large. Fully automated methods are able to perform very well for "easy" targets (85% sequence identity with parent), but when modeling using a distantly related parent, care and expertise, especially in performing the alignment, still appear to be important factors in generating accurate models.
Effective function annotation through catalytic residue conservation
Proceedings of the National Academy of Sciences of the United States of America, Jul 21, 2005
<i>PROCHECK</i>: validation of protein-structure coordinates
International Union of Crystallography eBooks, Apr 1, 2012
The structure-validation program PROCHECK is described. Keywords: PROCHECK; structure validation
Journal of Molecular Biology, Dec 1, 1996
Biomolecular Structure and The work described here is the result of a survey of the peptide v ang... more Biomolecular Structure and The work described here is the result of a survey of the peptide v angles in the Cambridge Structural Database of small molecules, which was Modelling Unit, Department of Biochemistry and carried out to establish ''ideal'' or ''target'' values for their distribution. We have shown that substantial deviations from planarity can be tolerated Molecular Biology with a standard deviation in the angle of up to 6°about a mean value for University College Gower Street, London the trans peptide that is less than 180°. The distortion can arise from pyramidalization at the amino nitrogen atom as well as simple twist about WC1E 6BT, England the peptide bond. We include an analysis of v angles in the existing database of protein structure (PDB) and show that their distributions can depend on the refinement method used, but no correlation with resolution is evident. A surprising finding was a systematic variation of v in f,c space in proteins as well as in the linear and cyclic peptides. This is particularly manifest as a consistent difference between the mean v values in chains of left and right-hand chirality. This dichotomy is observed for all the standard amino acids and is especially striking in the absence of secondary structure. The phenomenon is discussed in the context of theoretical work on peptide analogues, and the implications for protein conformation and structure are briefly considered.
Programs and program systems in wide use
International Union of Crystallography eBooks, 2006
... Furey, W., Cowtan, KD, Zhang, KYJ, Main, P., Brunger, AT, Adams, PD, DeLano, WL, Gros, P., Gr... more ... Furey, W., Cowtan, KD, Zhang, KYJ, Main, P., Brunger, AT, Adams, PD, DeLano, WL, Gros, P., Grosse‐Kunstleve, RW, Jiang, J.-S., Pannu, NS, Read, RJ, Rice ... Division of Basic Sciences, FredHutchinson Cancer Research Center, 1100 Fairview Ave N., Seattle, WA 90109, USA. ...
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 1993
The rapid increase in the number of high-quality protein structures provides an expanding knowled... more The rapid increase in the number of high-quality protein structures provides an expanding knowledge resource about interactions involved in stabilizing protein three-dimensional structures and the complexes they form with other molecules. In this paper we first review the results of some recent analyses of protein structure, including restrictions on local conformation, and a study of the geometry of hydrogen bonds. Then we consider how such empirical data can be used as a test bed for energy calculations, by using the observed spatial distributions of side chain/atom interactions to assess three different methods for modelling atomic interactions in proteins. We have also derived a new empirical solvation potential which aims to reproduce the hydrophobic effect. To conclude we address the problem of molecular recognition and consider what we can deduce about the interactions involved in the binding of peptides to proteins.
Journal of Biomolecular NMR, 1996
The AQUA and PROCHECK-NMR programs provide a means of validating the geometry and restraint viola... more The AQUA and PROCHECK-NMR programs provide a means of validating the geometry and restraint violations of an ensemble of protein structures solved by solution NMR. The outputs include a detailed breakdown of the restraint violations, a number of plots in PostScript format and summary statistics. These various analyses indicate both the degree of agreement of the model structures with the experimental data, and the quality of their geometrical properties. They are intended to be of use both to support ongoing NMR structure determination and in the validation of the final results.
PROCHECK: a program to check the stereochemical quality of protein structures
Journal of Applied Crystallography, 1993
The PROCHECK suite of programs provides a detailed check on the stereochemistry of a protein stru... more The PROCHECK suite of programs provides a detailed check on the stereochemistry of a protein structure. Its outputs comprise a number of plots in PostScript format and a comprehensive residue-by-residue listing. These give an assessment of the overall quality of the structure ...
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Papers by Malcolm W MacArthur