Causative to the neurodegenerative Huntington’s disease (HD), a mutational huntingtin (HTT) protein consists of an unusual expansion on the poly-glutamine (polyQ) region in the first exon (exon-1) domain. Despite its significance on HD progression, the structural role of the exon-1 with the polyQ region is still elusive. As HTT is an intrinsically disordered protein (IDP), a large ensemble of various conformations (instead of a mostly single native conformation) is required to characterize its structural properties and to infer biological functions, which is challenging even for the most state-of-the-art experimental techniques. For this reason, molecular dynamics (MD) simulations with enhanced sampling techniques are ideal to compliment experiment on collecting such a large ensemble of thermodynamically accessible structures. Here, we performed large-scale temperature replica-exchange MD (T-REMD) simulations on the exon-1 with an illustration on the necessity of using T-REMD instead of unbiased regular MD. By comparing T-REMD data and unbiased MD data, we discovered that (1) the dynamics of polyQ regions are extremely sluggish and glassy at the room temperature and the relaxation of the system cannot be achieved within a reasonable amount of time without utilizing an enhanced sampling method and (2) an ensemble of protein structures containing the surprising cis-peptide bonds in the proline-rich domain can be obtained at much elevated temperatures. Our results may provide valuable insights for future studies on the HTT as well as other IDPs using the T-REMD method.
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21 August 2018
Research Article|
July 17 2018
Glassy dynamics in mutant huntingtin proteins
Special Collection:
Enhanced Sampling for Molecular Systems
Hongsuk Kang
;
Hongsuk Kang
1
Institute of Quantitative Biology, Department of Physics, Zhejiang University
, Hangzhou 310027, China
2
Computational Biology Center, IBM Thomas J. Watson Research Center
, Yorktown Heights, New York 10598, USA
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Binquan Luan
;
Binquan Luan
2
Computational Biology Center, IBM Thomas J. Watson Research Center
, Yorktown Heights, New York 10598, USA
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Ruhong Zhou
Ruhong Zhou
a)
1
Institute of Quantitative Biology, Department of Physics, Zhejiang University
, Hangzhou 310027, China
2
Computational Biology Center, IBM Thomas J. Watson Research Center
, Yorktown Heights, New York 10598, USA
a)Author to whom correspondence should be addressed: ruhongz@us.ibm.com
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a)Author to whom correspondence should be addressed: ruhongz@us.ibm.com
J. Chem. Phys. 149, 072333 (2018)
Article history
Received:
March 13 2018
Accepted:
June 25 2018
Citation
Hongsuk Kang, Binquan Luan, Ruhong Zhou; Glassy dynamics in mutant huntingtin proteins. J. Chem. Phys. 21 August 2018; 149 (7): 072333. https://doi.org/10.1063/1.5029369
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