Arun Prasad Pandurangan

MRC Laboratory of Molecular Biology

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Maya Topf

University Medical Center Hamburg-Eppendorf

Tom L. Blundell

University of Cambridge

Julian Gough

MRC Laboratory of Molecular Biology

N. Gautham

University of Madras

Sarah J. Butcher

University of Helsinki

Daven Vasishtan

University of Oxford

Ian Sillitoe

University College London

Gustavo A Salazar

European Bioinformatics Institute

Irene Farabella

Centre for Genomic Regulation

Shabih Shakeel

MRC Laboratory of Molecular Biology

Cooperative Institutions

European Bioinformatics Institute

University College London

University of Cambridge

Institute of Structural and Molecular Biology

MRC Laboratory of Molecular Biology

Wellcome Sanger Institute

Tata Consultancy Services (India)

Wellcome Trust

University of Bristol

Indian Institute of Science Bangalore

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Hypothesis-free phenotype prediction within a genetics-first framework

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Chang Lu Jan Zaucha Rihab Gam Hai Fang Ben Smithers

Summary Cohort-wide sequencing studies have revealed that the largest category of variants is those deemed ‘rare’, even for the subset located in coding regions (99% of known coding variants are seen in less than 1% of the population 1–3 ). Our understanding of how rare genetic variants influence disease and organism-level phenotypes has achieved limited progress, partly explained by the intrinsic difficulty in statistically evaluating the biological significance of rare events. Here we show that discoveries can instead be made through a knowledge-based approach using protein domains and ontologies (function and phenotype) that considers all coding variants regardless of allele frequency. We describe an ab initio , genetics-first method making molecular knowledge-based interpretations for exome-wide non-synonymous variants for phenotypes at the organism and cellular level. By using this reverse approach, we identify plausible novel genetic causes for developmental disorders that have eluded other established methods and present novel molecular hypotheses for the causal genetics of 40 phenotypes generated from a direct-to-consumer genotype cohort. This system offers a chance to extract further discovery from genetic data after standard tools have been applied.

Genotype-phenotype distinction

Exome

10.1101/2023.02.01.526358

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Citations (0)

Exploring conformational space using a mean field technique with MOLS sampling

Journal of Biosciences (2007)

Arun Prasad Pandurangan Kanagasabai Vadivel J. Arunachalam N. Gautham

Maxima and minima

Loop modeling

Force Field

10.1007/s12038-007-0091-3

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Citations (6)

γ-TEMPy: Simultaneous Fitting of Components in 3D-EM Maps of Their Assembly Using a Genetic Algorithm

Structure (2015)

Arun Prasad Pandurangan Daven Vasishtan Frank Alber Maya Topf

We have developed a genetic algorithm for building macromolecular complexes using only a 3D-electron microscopy density map and the atomic structures of the relevant components. For efficient sampling the method uses map feature points calculated by vector quantization. The fitness function combines a mutual information score that quantifies the goodness of fit with a penalty score that helps to avoid clashes between components. Testing the method on ten assemblies (containing 3-8 protein components) and simulated density maps at 10, 15, and 20 Å resolution resulted in identification of the correct topology in 90%, 70%, and 60% of the cases, respectively. We further tested it on four assemblies with experimental maps at 7.2-23.5 Å resolution, showing the ability of the method to identify the correct topology in all cases. We have also demonstrated the importance of the map feature-point quality on assembly fitting in the lack of additional experimental information.

10.1016/j.str.2015.10.013

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Citations (35)

Coxsackievirus A7 (CAV7) full capsid reconstruction at 8.23 angstrom resolution.

Jani Seitsonen Shabih Shakeel Petri Susi Arun Prasad Pandurangan Robert S. Sinkovits

Coxsackievirus

Angstrom

10.2210/pdb4agx/pdb

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Genetic risk factors for death with SARS-CoV-2 from the UK Biobank

medRxiv (Cold Spring Harbor Laboratory) (2020)

Chang Lu Rihab Gam Arun Prasad Pandurangan Julian Gough

Abstract We present here genetic risk factors for survivability from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 19 (COVID-19). At the time of writing it is too early to determine comprehensively and without doubt all risk factors, but there is an urgency due to the global pandemic crisis that merits this early analysis. We have nonetheless discovered 5 novel risk variants in 4 genes, discovered by examining 193 deaths from 1,412 confirmed infections in a group of 5,871 UK Biobank participants tested for the virus. We also examine the distribution of these genetic variants across broad ethnic groups and compare it to data from the UK Office of National Statistics for increased risk of death from SARS-CoV-2. We confidently identify the gene ERAP2 with a high-risk variant, as well as three other genes of potential interest. Although mostly rare, a common theme of genetic risk factors affecting survival might be the inability to launch or modulate an effective immune and stress response to infection from the SARS-CoV-2 virus.

Pandemic

Coronavirus

10.1101/2020.07.01.20144592

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Citations (33)

In silico analyses of isoniazid and streptomycin resistance-associated mutations in Mycobacterium tuberculosis

Computational and Structural Biotechnology Journal (2023)

Rushikesh Singh Dasoondi Tom L. Blundell Arun Prasad Pandurangan

Multi-drug resistant tuberculosis is categorised by the World Health Organisation (WHO) as a public health crisis. In silico techniques were used to probe the structural basis of Mycobacterium tuberculosis resistance to isoniazid and streptomycin. Isoniazid resistance-associated mutations in InhA were predicted to reduce the binding affinity of NADH to InhA, without affecting INH-NAD (competitive-inhibitor) binding. Perturbation of the mutated residues was predicted (with the AlloSigMA server) to modulate the free energy of allosteric modulation of key binding site residues F41, F149, Y158 and W222. These results suggest that allosteric modulation of the protein structure may be key to the mechanism by which isoniazid resistance-associated mutations act. Mutations in the methyltransferase glucose-inhibited division gene B (GidB) are associated with streptomycin resistance. Molecular docking was carried out to predict the structure of the GidB bound to its substrate (s-adenosyl methionine). The effects of streptomycin resistance-associated mutations in GidB on protein stability and substrate binding were predicted (using SDM and mCSM-lig). All GidB mutants were predicted to disfavour SAM binding.

INHA

Docking (animal)

10.1016/j.csbj.2023.02.035

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Citations (3)

Finding rigid bodies in protein structures: Application to flexible fitting into cryoEM maps

Journal of Structural Biology (2011)

Arun Prasad Pandurangan Maya Topf

Benchmark (surveying)

10.1016/j.jsb.2011.10.011

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Citations (38)

Stepwise visualization of membrane pore formation by suilysin, a bacterial cholesterol-dependent cytolysin

eLife (2014)

Carl Leung Natalya V. Dudkina Natalya Lukoyanova Adrian W. Hodel Irene Farabella

Membrane attack complex/perforin/cholesterol-dependent cytolysin (MACPF/CDC) proteins constitute a major superfamily of pore-forming proteins that act as bacterial virulence factors and effectors in immune defence. Upon binding to the membrane, they convert from the soluble monomeric form to oligomeric, membrane-inserted pores. Using real-time atomic force microscopy (AFM), electron microscopy (EM), and atomic structure fitting, we have mapped the structure and assembly pathways of a bacterial CDC in unprecedented detail and accuracy, focussing on suilysin from Streptococcus suis. We show that suilysin assembly is a noncooperative process that is terminated before the protein inserts into the membrane. The resulting ring-shaped pores and kinetically trapped arc-shaped assemblies are all seen to perforate the membrane, as also visible by the ejection of its lipids. Membrane insertion requires a concerted conformational change of the monomeric subunits, with a marked expansion in pore diameter due to large changes in subunit structure and packing.

Cytolysin

10.7554/elife.04247

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Citations (156)

The Genome3D Consortium for Structural Annotations of Selected Model Organisms

Methods in molecular biology (2020)

Vaishali Waman Tom L. Blundell Daniel Buchan Julian Gough David T. Jones

Model Organism

10.1007/978-1-0716-0708-4_3

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Citations (12)

Coxsackievirus A7 (CAV7) empty capsid reconstruction at 6.09 angstrom resolution.