Abstract
Understanding and computationally predicting the protein folding process remains one of the most challenging scientific problems and has uniquely garnered the interdisciplinary efforts of researchers from both the biological, chemical, physical and computational disciplines. Previous studies have demonstrated the importance of long-range interactions in guiding the native structure. However, predicting how the native long-range interaction network forms to generate a specific topology from among all other conformations remains unresolved. The present research study conducts an exploratory study to identify amino acids and long-range interactions that have the potential to play a key role in building and maintaining the protein topology. Towards this end, the application of network science is utilized and developed to analyze the structures of a group of proteins that share a common Greek-key topology but differ in sequence, secondary structure and function. We investigate the idea that the residues with high betweeness centrality score are potentially significant in maintaining the protein network and in governing the Greek-key topology. This hypothesis is tested by two different computational methods: through a fragmentation test and by the analysis of diameter impacts. In summary, we find a subset of selected residues in similar geographical positions in all model proteins, which demonstrates the role of these specific residues and regions in governing the Greek-key topology from a network perspective.
Similar content being viewed by others
References
Higman VA, Greene LH (2006) Elucidation of conserved long-range interaction networks in proteins and their significance in determining protein topology. Phys A 368(2):595–606
Selvaraj S, Gromiha MM (2003) Role of hydrophobic clusters and long-range contact networks in the folding of ([alpha]/[beta])8 barrel proteins. Biophys J 84(3):1919–1925
Sengupta D, Kundu S (2012) Role of long- and short-range hydrophobic, hydrophilic and charged residues contact network in protein’s structural organization. BMC Bioinform 13:142–142
Gromiha MM, Selvaraj S (1999) Importance of long-range interactions in protein folding. Biophys Chem 77(1):49–68
Cregut D, Civera C, Macias MJ, Wallon G, Serrano L (1999) A tale of two secondary structure elements: when a β-hairpin becomes an α-helix. J Mol Biol 292(2):389–401
Dorogovtsev SN, Mendes JFF (2003) Evolution of networks: from biological nets to the internet and WWW. Oxford University Press, Oxford
Winn MD, Ballard CC, Cowtan KD, Dodson EJ, Emsley P, Evans PR, Keegan RM, Krissinel EB, Leslie AGW, McCoy A, McNicholas SJ, Murshudov GN, Pannu NS, Potterton EA, Powell HR, Read RJ, Vagin A, Wilson KS (2011) Overview of the CCP4 suite and current developments. Acta Crystallogr Sect D 67(4):235–242
Greene L, Higman V (2003) Uncovering network systems within protein structures. J Mol Biol 334:781–791
Di Paola L, Giuliani A (2015) Protein contact network topology: a natural language for allostery. Curr Opin Struct Biol 31:43–48
Miller EJ, Fischer KF, Marqusee S (2002) Experimental evaluation of topological parameters determining protein-folding rates. Proc Natl Acad Sci USA 99(16):10359–10363
Chen C, Li L, Xiao Y (2006) Identification of key residues in proteins by using their physical characters. Phys Rev E 73(4):041926
Li J, Wang J, Wang W (2008) Identifying folding nucleus based on residue contact networks of proteins. Proteins 71(4):1899–1907
Aftabuddin M, Kundu S (2007) Hydrophobic, hydrophilic, and charged amino acid networks within protein. Biophys J 93(1):225–231
Khor S (2018) Folding with a protein’s native shortcut network. Proteins 86(9):924–934
Yan W, Zhou J, Sun M, Chen J, Hu G, Shen B (2014) The construction of an amino acid network for understanding protein structure and function. Amino Acids 46(6):1419–1439
Berglund H, Olerenshaw D, Sankar A, Federwisch M, McDonald NQ, Driscoll PC (2000) The three-dimensional solution structure and dynamic properties of the human FADD death domain. J Mol Biol 302(1):171–188
Eberstadt M, Huang B, Chen Z, Meadows RP, Ng S-C, Zheng L, Lenardo MJ, Fesik SW (1998) NMR structure and mutagenesis of the FADD (Mort1) death-effector domain. Nature 392(6679):941–945
Humke EW, Shriver SK, Starovasnik MA, Fairbrother WJ, Dixit VM (2000) ICEBERG: a novel inhibitor of interleukin-1β generation. Cell 103(1):99–111
Gitschier J, Moffat B, Reilly D, Wood WI, Fairbrother WJ (1998) Solution structure of the fourth metal-binding domain from the Menkes copper-transporting ATPase. Nat Struct Biol 5(1):47–54
Lindahl M, Svensson LA, Liljas A, Sedelnikova SE, Eliseikina IA, Fomenkova NP, Nevskaya N, Nikonov SV, Garber MB, Muranova TA (1994) Crystal structure of the ribosomal protein S6 from Thermus thermophilus. EMBO J 13(6):1249–1254
Thunnissen MMGM, Taddei N, Liguri G, Ramponi G, Nordlund P (1997) Crystal structure of common type acylphosphatase from bovine testis. Structure 5(1):69–79
Improta S, Politou AS, Pastore A (1996) Immunoglobulin-like modules from titin I-band: extensible components of muscle elasticity. Structure 4(3):323–337
Holden HM, Ito M, Hartshorne DJ, Rayment I (1992) X-ray structure determination of telokin, the C-terminal domain of myosin light chain kinase, at 2.8 Å resolution. J Mol Biol 227(3):840–851
Leahy D, Hendrickson W, Aukhil I, Erickson H (1992) Structure of a fibronectin type III domain from tenascin phased by MAD analysis of the selenomethionyl protein. Science 258(5084):987–991
Vendruscolo M, Dokholyan NV, Paci E, Karplus M (2002) Small-world view of the amino acids that play a key role in protein folding. Phys Rev E 65(6):061910
Mrvar A, Batagelj V (2016) Analysis and visualization of large networks with program package Pajek. Complex Adapt Syst Model 4(1):6
de Nooy W, Mrvar A, Batagelj V (2011) Exploratory social network analysis, 2nd edn. Cambridge University Press, New York
Albert R, Jeong H, Barabási A-L (2000) Error and attack tolerance of complex networks. Nature 406(6794):378–382
Takes FW, Kosters WA (2011) Determining the diameter of small world networks. Paper presented at the Proceedings of the 20th ACM international conference on information and knowledge management, Glasgow, Scotland, UK
Greene LH (2012) Protein structure networks. Brief Funct Genom 11(6):469–478
Greene LH, Grant T (2012) Protein folding by ‘levels of separation’: a hypothesis. FEBS Lett 586:962–966
Fersht AR (1999) Structure and mechanism in protein science. WH Freeman and Company, New York
Fersht AR, Sato S (2004) Φ-Value analysis and the nature of protein-folding transition states. Proc Natl Acad Sci USA 101(21):7976–7981
Otzen DE, Oliveberg M (2002) Conformational plasticity in folding of the split β-α-β protein S6: evidence for burst-phase disruption of the native state. J Mol Biol 317(4):613–627
Fowler SB, Clarke J (2001) Mapping the folding pathway of an immunoglobulin domain: structural detail from phi value analysis and movement of the transition state. Structure 9(5):355–366
Steward A, McDowell GS, Clarke J (2009) Topology is the principal determinant in the folding of a complex all-alpha Greek key death domain from human FADD. J Mol Biol 389(2):425–437
Cota E, Steward A, Fowler SB, Clarke J (2001) The folding nucleus of a fibronectin type III domain is composed of core residues of the immunoglobulin-like fold. J Mol Biol 305(5):1185–1194
Chiti F, Taddei N, White PM, Bucciantini M, Magherini F, Stefani M, Dobson CM (1999) Mutational analysis of acylphosphatase suggests the importance of topology and contact order in protein folding. Nat Struct Mol Biol 6(11):1005–1009
Acknowledgements
This work is funded in part by the Natural Science Foundation of China under Grant No. 61728211 and National Science Foundation under Grant No. 1066471 (YL).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors do not have any conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Haratipour, Z., Aldabagh, H., Li, Y. et al. Network Connectivity, Centrality and Fragmentation in the Greek-Key Protein Topology. Protein J 38, 497–505 (2019). https://doi.org/10.1007/s10930-019-09850-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10930-019-09850-7