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Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

A Molecular Dynamics Simulation Based Prediction of Deleterious Angiogenin Mutations Causing Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons leading to paralysis and death between 3-5 years of diagnosis. Through whole genome association studies, several single nucleotide polymorphisms (SNPs) encoding missense mutations in angiogenin (ANG) protein have been identified as one of the primary factors causing ALS. Structural studies of ANG show that catalytic triad comprising His13, Lys40 and His114 residues imparts ribonucleolytic activity while nuclear localization signal residues 31RRR33 are responsible for nuclear translocation activity. Loss of either ribonucleolytic activity or nuclear translocation activity or both of these functions due to mutations cause ALS. However, the mechanisms of loss-of-functions of ANG mutants are not completely understood.

Here we present a cohesive and comprehensive picture of functional loss mechanisms of all known ALS associated ANG mutants by extensive molecular dynamics (MD) simulations [1, 2]. Our studies show that conformational switching of catalytic residue His114 is responsible for the loss of ribonucleolytic activity while reduction in solvent accessible surface area (SASA) of 31RRR33 as a result of local folding is responsible for the loss of nuclear translocation activity (Padhi et al. 2012, 2013). Our prediction of loss-of-functions of 17 ANG mutants correlated positively with the reported experimental results. We have subsequently developed a fast molecular dynamics method based on certain global attributes / dynamic markers that can be used to determine whether a mutation is deleterious or benign. To make our method accessible to researchers and clinicians, we created a web server based tool, ANGDelMut, freely available at http://bioschool.iitd.ernet.in/research.htm, where a user can submit new mutations to ascertain whether they cause ALS. We hope that our method will benefit the community at large and will pave the way for the development of a successful therapy for patients suffering from ALS.

References
Padhi AK, Kumar H, Vasaikar SV, Jayaram B & Gomes J (2012). Mechanisms of loss of functions of human angiogenin variants implicated in amyotrophic lateral sclerosis. PLoS One, 7(2): e32479.

Padhi AK, Jayaram B & Gomes J (2013). Prediction of Functional Loss of Human Angiogenin Mutants Associated with ALS by Molecular Dynamics Simulations. Sci. Rep. 3, 1225.

Aditya K. Padhi1
B. Jayaram 1,2,3
James Gomes1

1Kusuma School of Biological Sciences
2Department of Chemistry
3Supercomputing Facility for Bioinformatics and Computational Biology
Indian Institute of Technology Delhi
Hauz Khas
New Delhi - 110016, India.

adi.uoh@gmail.com
bjayaram@chemistry.iitd.ac.in
jgomes@bioschool.iitd.ac.in