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Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan's disease

Science China(Life Sciences) 2012年第12期55卷 1109-1119页

作者： sreevishnupriya k. CHANDRASEk.RAN P. SENTHILk.MAR A. SETHUMADHAVAN R. SHANTHI V. DAISY P. NISHA J. RAMANATHAN k. RAJASEk.RAN R. Bioinformatics Division School of Biosciences and Technology Vellore Institute of TechnologyVellore 632014 Tamil Nadu India Department of Biotechnology Holy Cross CollegeTrichy 620002 Tamil Nadu India

In this work. the most detrimental missense mutations of aspartoacylase that cause Canavan's disease were identified computationally and the substrate binding efficiencies of those missense mutations were analyzed. Out of 30 missense mutations, I-Mutant 2.0, SIFT and PolyPhen programs identified 22 variants that were less stable, deleterious and damaging respectively. Subsequently, modeling of these 22 variants was performed to understand the change in their conformations with respect to the native aspartoacylase by computing their root mean squared deviation (RMSD). Furthermore, the native protein and the 22 mutants were dock.d with the substrate NAA (N-Acetyl-Aspartic acid) to explain the substrate binding efficiencies of those detrimental missense mutations. Among the 22 mutants, the dock.ng studies identified that 15 mutants caused lower binding affinity for NAA than the native protein. Finally, normal mode analysis determined that the loss of binding affinity of these 15 mutants was caused by altered flexibility in the amino acids that bind to NAA compared with the native protein. Thus, the pre- sent study showed that the majority of the substrate-binding amino acids in those 15 mutants displayed loss of flexibility, which could be the theoretical explanation of decreased binding affinity between the mutant aspartoacylases and NAA.

关键词： missense mutation Canavan's disease aspartoacylase NAA flexibility

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

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Frontiers in Biology 2013年第6期8卷 618-625页

作者： Merlin LOPUS Rao SETHUMADHAVAN P. CHANDRASEk.RAN k. sreevishnupriya A.W. VARSHA V. SHANTHI k. RAMANATHAN R. RAJASEk.RAN Bioinformatics Division School of Biosciences and Technology Vellore Institute of Technology Vellore 632014 Tamil Nadu India Industrial Biotechnology Division School of Biosciences and Technology Vellore Institute of Technology Vellore 632014 Tamil Nadu India

In this work. the most detrimental missense mutations of Madl 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 Madl by computing their root mean squared deviation （RMSD）. Furthermore, the native protein and the 3 mutants were dock.d with the binding partner Mad2 to explain the substrate binding efficiencies of those detrimental missense mutations. The dock.ng 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 Madl and Mad2.

关键词： missense mutation Madl Mad2 spindle check.point cancer

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