LINUS: a hierarchic procedure to predict the fold of a protein
Abstract
We describe LINUS, a hierarchic procedure to predict the fold of a protein from its amino acid sequence alone. The algorithm, which has been implemented in a computer program, was applied to large, overlapping fragments from a diverse test set of 7 X-ray-elucidated proteins, with encouraging results. For all proteins but one, the overall fragment topology is well predicted, including both secondary and supersecondary structure. The algorithm was also applied to a molecule of unknown conformation, groES, in which X-ray structure determination is presently ongoing. LINUS is an acronym for Local Independently Nucleated Units of Structure. The procedure ascends the folding hierarchy in discrete stages, with concomitant accretion of structure at each step. The chain is represented by simplified geometry and folds under the influence of a primitive energy function. The only accurately described energetic quantity in this work is hard sphere repulsion--the principal force involved in organizing protein conformation [Richards, F. M. Ann. Rev. Biophys. Bioeng. 6:151-176, 1977]. Among other applications, the method is a natural tool for use in the human genome initiative.
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“This model is motivated by Srinivasan and Rose (60); it aims at reducing the effect of contacts that correspond to large native C-C native distances.”
BackgroundMethodInfluentialSampling Realistic Protein Conformations Using Local Structural Bias
Hamelryck, T., Kent, J. T., & Krogh, A. (2006) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0020131 · Cited by 119 · see citing works
“Markov Chain Monte Carlo (MCMC)–based methods [3,15,16] propose decoys that are accepted or rejected depending on their Boltzmann weights.”
MethodResultComputational methods in protein structure prediction
Floudas, C. A. (2007) · Biotechnology and Bioengineering · doi:10.1002/bit.21411 · Cited by 116 · see citing works
“Baker and co-workers studied the distributions of local structures based on short sequence segments of up to 10 residues based on the protein database, and developed effective approaches that compare fragments of a target to fragments of known structures.”
BackgroundA protein taxonomy based on secondary structure.
Rose, G. D., Przytycka, T. M., & Aurora, R. (1999) · Nature Structural Biology · doi:10.1038/10728 · Cited by 112 · see citing works
Osguthorpe, D. J. (2000) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(00)00067-1 · Cited by 110 · see citing works
Dima, R. I., & Thirumalai, D. (2002) · Biophysical Journal · doi:10.1016/s0006-3495(02)73899-x · Cited by 100 · see citing works
A fast conformational search strategy for finding low energy structures of model proteins
Beutler, T. C., & Dill, K. A. (1996) · Protein Science · doi:10.1002/pro.5560051010 · Cited by 97 · see citing works
Munson, P. J., & Singh, R. K. (1997) · Protein Science · doi:10.1002/pro.5560060711 · Cited by 97 · see citing works
Folding Very Short Peptides Using Molecular Dynamics
Ho, B. K., & Dill, K. A. (2006) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0020027 · Cited by 97 · see citing works
“First, simple physical models can reproduce the structural biases of certain peptide fragments [25–28].”
BackgroundForge, V., Hoshino, M., Kuwata, K., Arai, M., Kuwajima, K., Batt, C. A., & Goto, Y. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3515 · Cited by 97 · see citing works
Xiao, X., Shao, S., Ding, Y., Huang, Z.-D., Chen, X., & Chou, K. (2005) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2005.02.008 · Cited by 96 · see citing works
“, 1995; Chou, 2004), simulated annealing approach (Chou and Carlacci, 1991; Chou, 1992), to threading approach (Bryant and Altschul, 1995; Bryant and Lawrence, 1993; Jones and Thornton, 1996) and ab initio approach (Jones, 1997; Srinivasan and Rose, 1995; Yang and Honig, 1995).”
MethodSimulation of an Ensemble of Conformational Transitions in a United-Residue Model of Calmodulin
Zuckerman, D. M. (2004) · The Journal of Physical Chemistry B · doi:10.1021/jp0370730 · Cited by 90 · see citing works
Aromatic side‐chain interactions in proteins. I. Main structural features
Thomas, A., Meurisse, R., Charloteaux, B., & Brasseur, R. (2002) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.10190 · Cited by 89 · see citing works
“We have used the definitions of the nine types of turns as defined by Srinivasan et al.(17)”
MethodFolding proteins with a simple energy function and extensive conformational searching
Yue, K., & Dill, K. A. (1996) · Protein Science · doi:10.1002/pro.5560050209 · Cited by 88 · see citing works
“However, it is not clear whether either the method of Srinivasan and Rose (1995) or that of Sun et al. (1995) is consistent with the thermodynamic hypothesis, because Sun et al. use artificial native structure re-straints and Srinivasan and Rose use a hierarchical method to overcome computer…”
BackgroundHuang, E. S., Samudrala, R., & Ponder, J. W. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.2861 · Cited by 86 · see citing works
“…and selection problems concomitantly (Bowie & Eisenberg, 1994; Cui et al., 1998; Dandekar & Argos, 1996; Jones, 1997; Monge et al., 1995; Mumenthaler & Braun, 1995; Ortiz et al., 1998; Pedersen & Moult, 1997; Simons et al., 1997; Srinivasan & Rose, 1995; Sun et al., 1995; Wilson & Doniach, 1989).”
Redrawing the Ramachandran plot after inclusion of hydrogen-bonding constraints
Porter, L. L., & Rose, G. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014674107 · Cited by 85 · see citing works
“5 Å, (ii) C─O─H scalar angle ≥90°, and (iii) N─H─O scalar angle ≥100° (31).”
Thermal unfolding of small proteins with SH3 domain folding pattern
Knapp, S., Mattson, P. T., Christova, P., Berndt, K. D., Karshikoff, A. D., Vihinen, M., Smith, C. I. E., & Ladenstein, R. (1998) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(19980515)31:3 · Cited by 56 · see citing works
Harms, M. J., Schlessman, J. L., Chimenti, M. S., Sue, G. R., Damjanović, A., & Bertrand García‐Moreno, E. (2008) · Protein Science · doi:10.1110/ps.073397708 · Cited by 83 · see citing works
“Relative accessible surface areas were calculated by comparison to a model of the amino acid in an extended, blocked, Ala-X-Ala peptide generated using Ribosome 1.0 (Srinivasan and Rose 1995).”
MethodInfluentialPeterson, R. W., Dutton, P. L., & Wand, A. J. (2004) · Protein Science · doi:10.1110/ps.03250104 · Cited by 82 · see citing works
“This result is not new in that its importance has been noted in the form of indications that steric constraints are the driving force for organizing protein conformations (Richards 1977; Srinivasan and Rose 1995).”
BackgroundFleming, P. J., Fitzkee, N. C., Mezei, M., Srinivasan, R., & Rose, G. D. (2004) · Protein Science · doi:10.1110/ps.041047005 · Cited by 82 · see citing works
“The conditional hydrophobic accessible surface area (CHASA) of model peptides was calculated using modules from the LINUS suite of programs (Srinivasan and Rose 1995; Srinivasan et al. 2004) with an effective probe radius of 1.4 Å after first placing virtual oxygen atoms at suitable positions…”
MethodInfluentialSampling the Self-Assembly Pathways of KFFE Hexamers
Wei, G., Mousseau, N., & Derreumaux, P. (2004) · Biophysical Journal · doi:10.1529/biophysj.104.047688 · Cited by 78 · see citing works
“The secondary structure, computedusing thef andc angles of the two inner residues following the criteria of Srinivasan and Rose (1995), shows that ;72% of all monomeric structures adopt a random coil conformation and 28% a b-strand structure; the population of a-helical conformations is negligible (0.”
BackgroundLocal sequence-structure correlations in proteins
Bystroff, C., Simons, K. T., Han, K. F., & Baker, D. A. (1996) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(96)80117-0 · Cited by 77 · see citing works
Forced Folding and Structural Analysis of Metastable Proteins
Peterson, R. W., Anbalagan, K., Tommos, C., & Wand, A. J. (2004) · Journal of the American Chemical Society · doi:10.1021/ja047900q · Cited by 75 · see citing works
Protein Structure, Stability, and Folding
Murphy, K. P. (2001) · Humana Press eBooks · doi:10.1385/1592591930 · Cited by 75 · see citing works
Self‐consistently optimized statistical mechanical energy functions for sequence structure alignment
Koretke, K. K., Luthey-Schulten, Z. A., & Wolynes, P. G. (1996) · Protein Science · doi:10.1002/pro.5560050607 · Cited by 71 · see citing works
“Different types of hydrogen bonding energy terms have been described by other authors (Nishikawa & Matsuo, 1993; Srinivasan & Rose, 1995).”
BackgroundHistoplasma acquisition of calcium and expression of CBP1 during intracellular parasitism
Batanghari, J. W., Deepe, G. S., Di, E., & Goldman, W. E. (1998) · Molecular Microbiology · doi:10.1046/j.1365-2958.1998.00697.x · Cited by 70 · see citing works
“Using the computer program LINUS (Srinivasan and Rose, 1995), we predicted a secondary structure of CBP based on its primary amino acid sequence, as shown in Fig.”
MethodInfluentialAb initio prediction of protein structure using LINUS
Srinivasan, R., & Rose, G. D. (2002) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.10103 · Cited by 70 · see citing works
Panchenko, A. R., Luthey-Schulten, Z. A., Cole, R., & Wolynes, P. G. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.1205 · Cited by 70 · see citing works
“It was demonstrated earlier that using a set of short fragments (3 to 15 residues) one can rebuild the backbone of some proteins with a comparable accuracy to the foldon matching modelling (Rooman et al., 1991; Simon et al., 1991; Levitt, 1992; Unger & Sussman, 1993; Srinivasan & Rose, 1995).”
BackgroundUnified perspective on proteins: A physics approach
Banavar, J. R., Hoàng, T. X., Maritan, A., Seno, F., & Trovato, A. (2004) · Physical Review E · doi:10.1103/physreve.70.041905 · Cited by 69 · see citing works
Mimicking the folding pathway to improve homology-free protein structure prediction
DeBartolo, J., Colubri, A., Jha, A., Fitzgerald, J. E., Freed, K. F., & Sosnick, T. R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811363106 · Cited by 65 · see citing works
Perspectives in protein-fold recognition
Torda, A. E. (1997) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(97)80026-7 · Cited by 65 · see citing works
“This wording is deliberately vague as search methods include molecular dynamics and Monte Carlo simulations, genetic algorithms [7,8], hierarchical methods [9,10] or procedures similar to those used to generate structures based on NMR data [11,12].”
MethodThe breakthrough in protein structure prediction
Lupas, A. N., Pereira, J., Alva, V., Merino, F., Coles, M. P., & Hartmann, M. D. (2021) · Biochemical Journal · doi:10.1042/bcj20200963 · Cited by 64 · see citing works
Protein folding and association: In vitro studies for self-organization and targeting in the cell
Jaenicke, R. (1996) · Current topics in cellular regulation · doi:10.1016/s0070-2137(96)80008-2 · Cited by 62 · see citing works
Protein structure: what is it possible to predict now?
Finkelstein, A. V. (1997) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(97)80008-5 · Cited by 62 · see citing works
The current state of the art in protein structure prediction
Moult, J. (1996) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(96)80118-2 · Cited by 59 · see citing works
Integrative Structural Biology in the Era of Accurate Structure Prediction
Masrati, G., Landau, M., Ben-Tal, N., Lupas, A., Kosloff, M., & Kosinski, J. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167127 · Cited by 53 · see citing works
Alexandrov, N. N., & Fischer, D. (1996) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(199607)25:3 · Cited by 107 · see citing works
The single helix in protein L is largely disrupted at the rate-limiting step in folding
Kim, D. E., Qian, Y., Gladwin, S. T., Goldberg, J. M., & Baker, D. A. (1998) · Journal of Molecular Biology · doi:10.1006/jmbi.1998.2200 · Cited by 54 · see citing works
“…almost all protein tertiary structure prediction methods (Bowie & Eisenberg, 1994; Monge et al., 1994; Simons et al., 1997; Skolnick et al., 1997; Srinivasan & Rose, 1995) assemble tertiary structures hierarchically from predicted local structural elements, typically helices and strands; the…”
BackgroundSelf-Interactions of Strands and Sheets
Banavar, J. R., Gonzalez, O., Maddocks, J. H., & Maritan, A. (2003) · Journal of Statistical Physics · doi:10.1023/a:1021010526495 · Cited by 53 · see citing works
“(28) This self-tuning of length scales occurs naturally for proteins because the steric effects (29, 30 ) associated with the backbone and side chain atoms of the amino acids, on the one hand, lead to a tube like description and control the tube thickness and the same side chains, on the other hand,”
BackgroundEmpirical parameterization of a model for predicting peptide helix/coil equilibrium populations
Andersen, N. H., & Tong, H. (1997) · Protein Science · doi:10.1002/pro.5560060913 · Cited by 53 · see citing works
Reducing the computational complexity of protein folding via fragment folding and assembly
Haspel, N., Tsai, C., Wolfson, H. J., & Nussinov, R. (2003) · Protein Science · doi:10.1110/ps.0232903 · Cited by 52 · see citing works
“This idea was further expanded by Srinivasan and Rose (1995, 1999).”
Computational Molecular Biology
Wong, W. H. (2000) · Journal of the American Statistical Association · doi:10.2307/2669558 · Cited by 52 · see citing works
Dunbrack, R. L., Gerloff, D. L., Bower, M. J., Chen, X., Lichtarge, O., & Cohen, F. E. (1997) · Folding and Design · doi:10.1016/s1359-0278(97)00011-4 · Cited by 52 · see citing works
Cavity formation before stable hydrogen bonding in the folding of a β-clam protein
Clark, P. L., Liu, Z., Rizo, J., & Gierasch, L. M. (1997) · Nature Structural & Molecular Biology · doi:10.1038/nsb1197-883 · Cited by 51 · see citing works
Structures, basins, and energies: A deconstruction of the Protein Coil Library
Perskie, L. L., Street, T. O., & Rose, G. D. (2008) · Protein Science · doi:10.1110/ps.035055.108 · Cited by 49 · see citing works
“LINUS: A hierarchic procedure to predict the fold of a protein.”
InfluentialVilloutreix, B. O., Dahlb�ck, B., Borgel, D., Gandrille, S., & Muller, Y. A. (2001) · Proteins Structure Function and Bioinformatics · doi:10.1002/1097-0134(20010501)43:2 · Cited by 26 · see citing works
Huang, E. S., Koehl, P., Levitt, M., Pappu, R. V., & Ponder, J. W. (1998) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(19981101)33:2 · Cited by 49 · see citing works
Hydrogen‐bonded turns in proteins: The case for a recount
Panasik, N., Fleming, P. J., & Rose, G. D. (2005) · Protein Science · doi:10.1110/ps.051625305 · Cited by 48 · see citing works
“Remaining trial conformations were then evaluated for steric clash using published hard-sphere radii (Srinivasan and Rose 1995).”
Sterics and Solvation Winnow Accessible Conformational Space for Unfolded Proteins
Fitzkee, N. C., & Rose, G. D. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.08.062 · Cited by 46 · see citing works
Aromatic side-chain interactions in proteins. Near- and far-sequence His–X pairs
Meurisse, R., Brasseur, R., & Thomas, A. (2003) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/s1570-9639(03)00161-4 · Cited by 46 · see citing works
Benner, S. A., Cannarozzi, G. M., Gerloff, D. L., Turcotte, M., & Chelvanayagam, G. (1997) · Chemical Reviews · doi:10.1021/cr940469a · Cited by 46 · see citing works
Computer simulations aimed at structure prediction of supersecondary motifs in proteins
Forcellino, F., & Derreumaux, P. (2001) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.1135 · Cited by 45 · see citing works
“9 This method does not consider any information such as a library of fragments 11,12 and multiple sequence alignments.”
MethodDerreumaux, P. (1997) · The Journal of Chemical Physics · doi:10.1063/1.473525 · Cited by 45 · see citing works
Knowledge-based potentials for protein folding: what can we learn from known protein structures?
Godzik, A. (1996) · Structure · doi:10.1016/s0969-2126(96)00041-x · Cited by 45 · see citing works
Protein folding for realists: A timeless phenomenon
Shortle, D., Wang, Y., Gillespie, J. R., & Wrabl, J. O. (1996) · Protein Science · doi:10.1002/pro.5560050602 · Cited by 45 · see citing works
Borguesan, B., Silva, M. B. E., Grisci, B. I., Inostroza-Ponta, M., & Dorn, M. (2015) · Computational Biology and Chemistry · doi:10.1016/j.compbiolchem.2015.08.006 · Cited by 44 · see citing works
“…M a nu sc r i p ( i ) first principle methods without database information (Osguthorpe, 2000); ( ii ) first principle methods with database information (Srinivasan and Rose, 1995; Rohl et al., 2004); ( iii ) threading or fold recognition methods (Bowie et al., 1991; Jones et al., 1992; Bryant and…”
MethodAromatic side‐chain interactions in proteins. II. Near‐ and far‐sequence Phe‐X pairs
Thomas, A., Meurisse, R., & Brasseur, R. (2002) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.10191 · Cited by 44 · see citing works
A rapid test for identification of autonomous folding units in proteins
Fischer, K. F., & Marqusee, S. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.4049 · Cited by 43 · see citing works
Koliński, A., Jaroszewski, L., Rotkiewicz, P., & Skolnick, J. (1998) · The Journal of Physical Chemistry B · doi:10.1021/jp973371j · Cited by 42 · see citing works
Helix capping in the GCN4 leucine zipper
Lu, M., Shu, W., Ji, H., Spek, E. J., Wang, L., & Kallenbach, N. R. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.2707 · Cited by 43 · see citing works
Protein Structure and Energy Landscape Dependence on Sequence Using a Continuous Energy Function
Dill, K. A., Phillips, A. T., & Rosen, J. B. (1997) · Journal of Computational Biology · doi:10.1089/cmb.1997.4.227 · Cited by 43 · see citing works
“Simplified potential functions have been successful in studies by Sun et al (1995), by Srinivasan and Rose (1995), and by Yue and Dill (1996).”
Research challenges, opportunities and synergism in systems engineering and computational biology
Floudas, C. A. (2005) · AIChE Journal · doi:10.1002/aic.10620 · Cited by 43 · see citing works
Dorn, M., Braga, A. L. S., Llanos, C. H., & Coelho, L. D. S. (2012) · Expert Systems with Applications · doi:10.1016/j.eswa.2012.04.046 · Cited by 41 · see citing works
Simmerling, C. L., Lee, M. R., Ortíz, Á. R., Koliński, A., Skolnick, J., & Kollman, P. A. (2000) · Journal of the American Chemical Society · doi:10.1021/ja993119k · Cited by 42 · see citing works
Sisyphus and prediction of protein structure
Rost, B., & O’Donoghue, S. I. (1997) · Computer applications in the biosciences · doi:10.1093/bioinformatics/13.4.345 · Cited by 42 · see citing works
“Srinivasan and Rose (1995) have reported very encouraging results with their hierarchical search method; however, they have not repeated the initial claims, so it may be that the initial report was too optimistic.”
ResultPaiz, E. A., Allen, J. H., Correia, J. J., Fitzkee, N. C., Hough, L. E., & Whitten, S. T. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101343 · Cited by 38 · see citing works
“Computer generated structures, described above, were processed using the CHASA module (76) of the LINUS software package (120, 121).”
MethodFolding a 20 amino acid αβ peptide with the diffusion process-controlled Monte Carlo method
Derreumaux, P. (1997) · The Journal of Chemical Physics · doi:10.1063/1.474546 · Cited by 41 · see citing works
Whisstock, J. C., Lesk, A. M., & Carrell, R. W. (1996) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(199611)26:3 · Cited by 30 · see citing works
- Authors
- Srinivasan, R., & Rose, G. D.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Rose, George D.
- ORCID
- Rose, George D.
- Venue
- Proteins Structure Function and Bioinformatics
- Publisher
- Wiley
- Published
- 1995-06
- Volume
- 22
- Issue
- 2
- Pages
- 81-99
- ISSN
- 0887-3585 (ISSN-L)
- 1097-0134
- OpenAlex
- W2132820390
- Cited by
- 266
- References
- 77
- Citations by year
- 2025: 1 · 2021: 5 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 4 · 2013: 4 · 2012: 5
- FWCI
- 12.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Proteins Structure Function and Bioinformatics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM-29458, R01GM029458)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
- Keywords
- Linus, protein fold prediction, secondary structure prediction, supersecondary structure, hard-sphere repulsion, GroES, Human Genome Project
- MeSH terms
- Algorithms, Amino Acids, Apoproteins, Base Sequence, Carrier Proteins, Computer Simulation, Cytochrome b Group, Models, Molecular, Molecular Sequence Data, Myoglobin, Neoplasm Proteins, Plastocyanin, Tetrahydrofolate Dehydrogenase, Thermodynamics, Molecular Structure, Serpins, Protein Structure, Secondary, Protein Folding, Crystallography, X-Ray, Chaperonin 10, Myelin P2 Protein, Escherichia coli Proteins, Fatty Acid-Binding Proteins
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