Comparative Exploratory Analysis of Intrinsically Disordered Protein Dynamics Using Machine Learning and Network Analytic Methods

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2019 Jun 28

PMID 31245383

Citations 14

Authors

Gianmarc Grazioli

Rachel W Martin

Carter T Butts

Affiliations

Soon will be listed here.

Abstract

Simulations of intrinsically disordered proteins (IDPs) pose numerous challenges to comparative analysis, prominently including highly dynamic conformational states and a lack of well-defined secondary structure. Machine learning (ML) algorithms are especially effective at discriminating among high-dimensional inputs whose differences are extremely subtle, making them well suited to the study of IDPs. In this work, we apply various ML techniques, including support vector machines (SVM) and clustering, as well as related methods such as principal component analysis (PCA) and protein structure network (PSN) analysis, to the problem of uncovering differences between configurational data from molecular dynamics simulations of two variants of the same IDP. We examine molecular dynamics (MD) trajectories of wild-type amyloid beta (Aβ) and its "Arctic" variant (E22G), systems that play a central role in the etiology of Alzheimer's disease. Our analyses demonstrate ways in which ML and related approaches can be used to elucidate subtle differences between these proteins, including transient structure that is poorly captured by conventional metrics.

Citing Articles

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Genetic Algorithm for Automated Parameterization of Network Hamiltonian Models of Amyloid Fibril Formation.

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Clustering Heterogeneous Conformational Ensembles of Intrinsically Disordered Proteins with t-Distributed Stochastic Neighbor Embedding.

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Circuit Topology Approach for the Comparative Analysis of Intrinsically Disordered Proteins.

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References

Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H . The Protein Data Bank. Nucleic Acids Res. 1999; 28(1):235-42. PMC: 102472. DOI: 10.1093/nar/28.1.235. View

Atilgan A, Durell S, Jernigan R, Demirel M, Keskin O, Bahar I . Anisotropy of fluctuation dynamics of proteins with an elastic network model. Biophys J. 2001; 80(1):505-15. PMC: 1301252. DOI: 10.1016/S0006-3495(01)76033-X. View

Jacobs D, Rader A, Kuhn L, Thorpe M . Protein flexibility predictions using graph theory. Proteins. 2001; 44(2):150-65. DOI: 10.1002/prot.1081. View

Nilsberth C, Westlind-Danielsson A, Eckman C, Condron M, Axelman K, Forsell C . The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001; 4(9):887-93. DOI: 10.1038/nn0901-887. View

Bolhuis P, Chandler D, Dellago C, Geissler P . Transition path sampling: throwing ropes over rough mountain passes, in the dark. Annu Rev Phys Chem. 2002; 53:291-318. DOI: 10.1146/annurev.physchem.53.082301.113146. View

Iakoucheva L, Brown C, Lawson J, Obradovic Z, Dunker A . Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol. 2002; 323(3):573-84. DOI: 10.1016/s0022-2836(02)00969-5. View

Teilum K, Kragelund B, Poulsen F . Transient structure formation in unfolded acyl-coenzyme A-binding protein observed by site-directed spin labelling. J Mol Biol. 2002; 324(2):349-57. DOI: 10.1016/s0022-2836(02)01039-2. View

Schwede T, Kopp J, Guex N, Peitsch M . SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res. 2003; 31(13):3381-5. PMC: 168927. DOI: 10.1093/nar/gkg520. View

Dedmon M, Lindorff-Larsen K, Christodoulou J, Vendruscolo M, Dobson C . Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations. J Am Chem Soc. 2005; 127(2):476-7. DOI: 10.1021/ja044834j. View

10.

Bernard C, Houben K, Derix N, Marks D, van der Horst M, Hellingwerf K . The solution structure of a transient photoreceptor intermediate: Delta25 photoactive yellow protein. Structure. 2005; 13(7):953-62. DOI: 10.1016/j.str.2005.04.017. View

11.

Brinda K, Vishveshwara S . A network representation of protein structures: implications for protein stability. Biophys J. 2005; 89(6):4159-70. PMC: 1366981. DOI: 10.1529/biophysj.105.064485. View

12.

Roccatano D, Sbardella G, Aschi M, Amicosante G, Bossa C, Di Nola A . Dynamical aspects of TEM-1 beta-lactamase probed by molecular dynamics. J Comput Aided Mol Des. 2005; 19(5):329-40. DOI: 10.1007/s10822-005-7003-0. View

13.

Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E . Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16):1781-802. PMC: 2486339. DOI: 10.1002/jcc.20289. View

14.

Lord A, Kalimo H, Eckman C, Zhang X, Lannfelt L, Nilsson L . The Arctic Alzheimer mutation facilitates early intraneuronal Abeta aggregation and senile plaque formation in transgenic mice. Neurobiol Aging. 2005; 27(1):67-77. DOI: 10.1016/j.neurobiolaging.2004.12.007. View

15.

Cecchini M, Curcio R, Pappalardo M, Melki R, Caflisch A . A molecular dynamics approach to the structural characterization of amyloid aggregation. J Mol Biol. 2006; 357(4):1306-21. DOI: 10.1016/j.jmb.2006.01.009. View

16.

Williamson J, Miranker A . Direct detection of transient alpha-helical states in islet amyloid polypeptide. Protein Sci. 2006; 16(1):110-7. PMC: 2222845. DOI: 10.1110/ps.062486907. View

17.

Young T, Abel R, Kim B, Berne B, Friesner R . Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding. Proc Natl Acad Sci U S A. 2007; 104(3):808-13. PMC: 1783395. DOI: 10.1073/pnas.0610202104. View

18.

Song J, Guo L, Muradov H, Artemyev N, Ruoho A, Markley J . Intrinsically disordered gamma-subunit of cGMP phosphodiesterase encodes functionally relevant transient secondary and tertiary structure. Proc Natl Acad Sci U S A. 2008; 105(5):1505-10. PMC: 2234174. DOI: 10.1073/pnas.0709558105. View

19.

Scholkopf B, Mika S, Burges C, Knirsch P, Muller K, Ratsch G . Input space versus feature space in kernel-based methods. IEEE Trans Neural Netw. 2008; 10(5):1000-17. DOI: 10.1109/72.788641. View

20.

Handcock M, Hunter D, Butts C, Goodreau S, Morris M . statnet: Software Tools for the Representation, Visualization, Analysis and Simulation of Network Data. J Stat Softw. 2008; 24(1):1548-7660. PMC: 2447931. DOI: 10.18637/jss.v024.i01. View