The morph server: a standardized system for analyzing and visualizing macromolecular motions in a database framework.

The number of solved structures of macromolecules that have the same fold and thus exhibit some degree of conformational variability is rapidly increasing. It is consequently advantageous to develop a standardized terminology for describing this variability and automated systems for processing protein structures in different conformations. We have developed such a system as a 'front-end' server to our database of macromolecular motions. Our system attempts to describe a protein motion as a rigid-body rotation of a small 'core' relative to a larger one, using a set of hinges. The motion is placed in a standardized coordinate system so that all statistics between any two motions are directly comparable. We find that while this model can accommodate most protein motions, it cannot accommodate all; the degree to which a motion can be accommodated provides an aid in classifying it. Furthermore, we perform an adiabatic mapping (a restrained interpolation) between every two conformations. This gives some indication of the extent of the energetic barriers that need to be surmounted in the motion, and as a by-product results in a 'morph movie'. We make these movies available over the Web to aid in visualization. Many instances of conformational variability occur between proteins with somewhat different sequences. We can accommodate these differences in a rough fashion, generating an 'evolutionary morph'. Users have already submitted hundreds of examples of protein motions to our server, producing a comprehensive set of statistics. So far the statistics show that the median submitted motion has a rotation of approximately 10 degrees and a maximum Calpha displacement of 17 A. Almost all involve at least one large torsion angle change of >140 degrees. The server is accessible at http://bioinfo.mbb.yale. edu/MolMovDB

[1]  Mark Gerstein,et al.  Studying Macromolecular Motions in a Database Framework: From Structure to Sequence , 2002 .

[2]  M. Gerstein,et al.  Assessing annotation transfer for genomics: quantifying the relations between protein sequence, structure and function through traditional and probabilistic scores. , 2000, Journal of molecular biology.

[3]  A. Crofts,et al.  Pathways for proton release during ubihydroquinone oxidation by the bc(1) complex. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  V S Pande,et al.  Molecular dynamics simulations of unfolding and refolding of a beta-hairpin fragment of protein G. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  S J Remington,et al.  Crystal structures of Escherichia coli glycerol kinase variant S58-->W in complex with nonhydrolyzable ATP analogues reveal a putative active conformation of the enzyme as a result of domain motion. , 1999, Biochemistry.

[6]  V S Pande,et al.  Folding pathway of a lattice model for proteins. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[7]  P B Sigler,et al.  GroEL/GroES: structure and function of a two-stroke folding machine. , 1998, Journal of structural biology.

[8]  S J Remington,et al.  Glycerol kinase from Escherichia coli and an Ala65-->Thr mutant: the crystal structures reveal conformational changes with implications for allosteric regulation. , 1998, Structure.

[9]  J. Tainer,et al.  Screening a peptidyl database for potential ligands to proteins with side‐chain flexibility , 1998, Proteins.

[10]  C Vonrhein,et al.  The structure of a trimeric archaeal adenylate kinase. , 1998, Journal of molecular biology.

[11]  M. Gerstein,et al.  A database of macromolecular motions. , 1998, Nucleic acids research.

[12]  A. Crofts,et al.  Structure and function of the cytochrome bc1 complex of mitochondria and photosynthetic bacteria. , 1998, Current opinion in structural biology.

[13]  M. Levitt,et al.  A unified statistical framework for sequence comparison and structure comparison. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J Vandekerckhove,et al.  Analysis of three human interleukin 5 structures suggests a possible receptor binding mechanism , 1998, FEBS letters.

[15]  M Levitt,et al.  Comprehensive assessment of automatic structural alignment against a manual standard, the scop classification of proteins , 1998, Protein science : a publication of the Protein Society.

[16]  A. Horwich,et al.  Structure and function in GroEL-mediated protein folding. , 1998, Annual review of biochemistry.

[17]  Tim J. P. Hubbard,et al.  SCOP: a structural classification of proteins database , 1998, Nucleic Acids Res..

[18]  M Gerstein,et al.  A structural census of genomes: comparing bacterial, eukaryotic, and archaeal genomes in terms of protein structure. , 1997, Journal of molecular biology.

[19]  Samuel H. Wilson,et al.  Crystal structures of human DNA polymerase beta complexed with gapped and nicked DNA: evidence for an induced fit mechanism. , 1997, Biochemistry.

[20]  L. Stryer,et al.  Molecular mechanics of calcium–myristoyl switches , 1997, Nature.

[21]  K Schulten,et al.  Protein domain movements: detection of rigid domains and visualization of hinges in comparisons of atomic coordinates , 1997, Proteins.

[22]  A. Horwich,et al.  Distinct actions of cis and trans ATP within the double ring of the chaperonin GroEL , 1997, Nature.

[23]  A. Horwich,et al.  The crystal structure of the asymmetric GroEL–GroES–(ADP)7 chaperonin complex , 1997, Nature.

[24]  Wilfried Schildkamp,et al.  Structure of a Protein Photocycle Intermediate by Millisecond Time-Resolved Crystallography , 1997, Science.

[25]  R Abagyan,et al.  A new method for modeling large‐scale rearrangements of protein domains , 1997, Proteins.

[26]  G J Kleywegt,et al.  Phi/psi-chology: Ramachandran revisited. , 1996, Structure.

[27]  S H Bryant,et al.  A dynamic look at structures: WWW-Entrez and the Molecular Modeling Database. , 1996, Trends in biochemical sciences.

[28]  J. Sussman,et al.  Site‐directed mutants designed to test back‐door hypotheses of acetylcholinesterase function , 1996, FEBS letters.

[29]  T. Tanaka,et al.  Nuclear Magnetic Resonance Evidence for Ca-induced Extrusion of the Myristoyl Group of Recoverin (*) , 1995, The Journal of Biological Chemistry.

[30]  D Eisenberg,et al.  3D domain swapping: A mechanism for oligomer assembly , 1995, Protein science : a publication of the Protein Society.

[31]  R A Sayle,et al.  RASMOL: biomolecular graphics for all. , 1995, Trends in biochemical sciences.

[32]  M. Gerstein,et al.  Average core structures and variability measures for protein families: application to the immunoglobulins. , 1995, Journal of molecular biology.

[33]  L. Stryer,et al.  Sequestration of the membrane-targeting myristoyl group of recoverin in the calcium-free state , 1995, Nature.

[34]  G J Kleywegt,et al.  Where freedom is given, liberties are taken. , 1995, Structure.

[35]  G. Schulz,et al.  Movie of the structural changes during a catalytic cycle of nucleoside monophosphate kinases. , 1995, Structure.

[36]  A G Murzin,et al.  SCOP: a structural classification of proteins database for the investigation of sequences and structures. , 1995, Journal of molecular biology.

[37]  Stephen H. Bryant,et al.  MMDB: An ASN.1 Specification for Macromolecular Structure , 1995, ISMB.

[38]  Samuel H. Wilson,et al.  Crystal structure of rat DNA polymerase beta: evidence for a common polymerase mechanism. , 1994, Science.

[39]  A. Lesk,et al.  Structural mechanisms for domain movements in proteins. , 1994, Biochemistry.

[40]  D. Eisenberg,et al.  Domain swapping: entangling alliances between proteins. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J L Sussman,et al.  Open "back door" in a molecular dynamics simulation of acetylcholinesterase. , 1994, Science.

[42]  J. Sussman,et al.  An electrostatic mechanism for substrate guidance down the aromatic gorge of acetylcholinesterase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Axel T. Brunger,et al.  X-PLOR Version 3.1: A System for X-ray Crystallography and NMR , 1992 .

[44]  A B Thompson,et al.  Aerosolized beclomethasone in chronic bronchitis. Improved pulmonary function and diminished airway inflammation. , 1992, The American review of respiratory disease.

[45]  Arthur M. Lesk,et al.  Protein Architecture: A Practical Approach , 1991 .

[46]  P. Kraulis.  A program to produce both detailed and schematic plots of protein structures , 1991 .

[47]  M Gerstein,et al.  Analysis of protein loop closure. Two types of hinges produce one motion in lactate dehydrogenase. , 1991, Journal of molecular biology.

[48]  M. Sternberg,et al.  Flexible protein sequence patterns. A sensitive method to detect weak structural similarities. , 1990, Journal of molecular biology.

[49]  G. Barton.  Protein multiple sequence alignment and flexible pattern matching. , 1990, Methods in enzymology.

[50]  K. Moffat.  Time-resolved macromolecular crystallography , 1996 .

[51]  M. Sternberg,et al.  A strategy for the rapid multiple alignment of protein sequences. Confidence levels from tertiary structure comparisons. , 1987, Journal of molecular biology.

[52]  M Karplus,et al.  Interdomain motion in liver alcohol dehydrogenase. Structural and energetic analysis of the hinge bending mode. , 1979, The Journal of biological chemistry.

[53]  K Nagayama,et al.  [Dynamics proteins]. , 1985, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[54]  J A McCammon,et al.  Large‐amplitude bending motions in phenylalanine transfer RNA , 1984, Biopolymers.

[55]  A M Lesk,et al.  Mechanisms of domain closure in proteins. , 1984, Journal of molecular biology.

[56]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[57]  William N. Lipscomb,et al.  Acceleration of reactions by enzymes , 1982 .

[58]  J. Sykes,et al.  Plasma lactoferrin levels in pregnancy and cystic fibrosis. , 1982, Clinica chimica acta; international journal of clinical chemistry.

[59]  T. A. Jones,et al.  Structure of a triclinic ternary complex of horse liver alcohol dehydrogenase at 2.9 A resolution. , 1981, Journal of molecular biology.