A computational approach to explore the functional missense mutations in the spindle check point protein Mad1

doi:10.1007/s11515-013-1280-0

Front Biol

2013, Vol. 8

Issue (6) : 618-625 https://doi.org/10.1007/s11515-013-1280-0

RESEARCH ARTICLE

A computational approach to explore the functional missense mutations in the spindle check point protein Mad1

Merlin LOPUS¹, Rao SETHUMADHAVAN¹, P. CHANDRASEKARAN¹, K. SREEVISHNUPRIYA¹, A.W. VARSHA², V. SHANTHI², K. RAMANATHAN¹, R. RAJASEKARAN¹(

)

1. Bioinformatics Division, School of Biosciences and Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India; 2. Industrial Biotechnology Division, School of Biosciences and Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India

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Abstract

In this work, the most detrimental missense mutations of Mad1 protein that cause various types of cancer were identified computationally and the substrate binding efficiencies of those missense mutations were analyzed. Out of 13 missense mutations, I Mutant 2.0, SIFT and PolyPhen programs identified 3 variants that were less stable, deleterious and damaging respectively. Subsequently, modeling of these 3 variants was performed to understand the change in their conformations with respect to the native Mad1 by computing their root mean squared deviation (RMSD). Furthermore, the native protein and the 3 mutants were docked with the binding partner Mad2 to explain the substrate binding efficiencies of those detrimental missense mutations. The docking studies identified that all the 3 mutants caused lower binding affinity for Mad2 than the native protein. Finally, normal mode analysis determined that the loss of binding affinity of these 3 mutants was caused by altered flexibility in the amino acids that bind to Mad2 compared with the native protein. Thus, the present study showed that majority of the substrate binding amino acids in those 3 mutants displayed loss of flexibility, which could be the theoretical explanation of decreased binding affinity between the mutant Mad1 and Mad2.

Keywords missense mutation Mad1 Mad2 spindle check point cancer

Corresponding Author(s): RAJASEKARAN R.,Email:rrajasekaran@vit.ac.in

Issue Date: 01 December 2013

Cite this article:

Merlin LOPUS,Rao SETHUMADHAVAN,P. CHANDRASEKARAN, et al. A computational approach to explore the functional missense mutations in the spindle check point protein Mad1[J]. Front Biol, 2013, 8(6): 618-625.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-013-1280-0
https://academic.hep.com.cn/fib/EN/Y2013/V8/I6/618

Tab.1 List of variants that were predicted to be functionally significant by I Mutant 2.0, SIFT and PolyPhen

Fig.1 Pymol view of (A) superimposed structure of the mutant R556C (cyan) with native (green), (B) superimposed structure of the mutant E511K (blue) with native (green), (C) superimposed structure of the mutant R556H (magenta) with native (green).

Tab.2 Total energy, RMSD, Atomic contact energy and intermolecular interactions for native and mutants of Mad1

Tab.3 Comparison of normalized mean square displacement of substrate binding amino acids of native and mutant Mad1 protein

Fig.2 Pymol view of (A) docked structure of the native Mad1 (green) with Mad 2 (grey), (B) docked structure of the mutant E511K (blue) with Mad 2 (grey) , (C) docked structure of the mutant R556C (cyan) with Mad 2 (grey), (D) docked structure of the mutant R556H (magenta) with Mad 2 (grey).

Tab.4 Binding amino acids of mutants with different ranges of flexibility based on<>

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