Mots-Clés

Bioinformatics Conformational dynamics Graph analysis Spike glycoprotein

Description

Description

The Covid-19 global pandemic emerged in late 2019, caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The major cellular infection mechanism of the virus is triggered by the interactions between the receptor binding domain (RBD) of the SARS-COV-2 Spike glycoprotein and the human ACE2 protein. Such interaction happens when the RBD undergoes large conformational changes from the closed conformation to the open conformation. Many mutations of SARS-CoV-2 have emerged independently worldwide because of its rapid viral replication. Among those mutations, the set of viral variants with mutations within the RBD and increased binding affinity toward ACE2 are called the variants of concern (VOC) for SARS-CoV-2 [1]. Each of these variants behave differently, such as being highly transmissible, more difficult to be diagnosed, having higher resistance, causing severe symptoms, etc. Therefore, having an in-depth understanding of these variants and the effect of mutations is highly crucial to develop therapeutic strategies against Covid-19. 

Molecular dynamics (MD) simulations are a powerful computational method that can assist in elucidating the dynamic behaviour of complex systems. Previously in the group, MD simulations of spike trimer in contact with ACE2 and its membrane were carried out for the original and other variants of concern. The system also includes the large set of glycans that cover the surface of Spike and ACE2 and are crucial for targeting the interactions between the two proteins. Each simulation consists of 1.5 µs all-atom explicit solvent MD simulation. The trajectories were recorded every 100ps, each of which consisting of 3.5 M atoms.

In this internship the goal is to design and implement a generic analysis workflow to investigate the set of generated trajectories and dissect the conformational dynamics of different variants in a systematic way. This is of high importance specifically due to the complexity of the system and large size of the produced data that has to be analyzed. Examples of computational methods to be integrated in the workflow and developed by us are: i) perturbation contact network analysis [1], ii) COMMA to describe dynamical architecture of proteins [2], and iii) Infostery to characterize mutational landscape of proteins [3]. These methods are based on the analysis of communication graphs to integrate dynamical correlations of every simulation and describe the interactions between different domains. Special attention will be brought to the comparison of the results obtained with each method and to the synthesis of these results.  Such study will allow us to better understand the dynamics of every variant and to underline the role of different mutations.

Objectives

- Identifying key regions for the interaction between RBD and ACE2
- Identifying potential allosteric communications within the spike structure
- Understanding the role of mutations and highlighting their differences

Required Skills

The Master 2 candidate should have a background in Computer Science, Bioinformatics, Chemoinformatics or a related master program and satisfy the following criteria:

- Programming skills, Python or R 
- Skills in algorithm design and graph theory
- Familiarity with Unix environment
- Basic knowledge in Bioinformatics/Chemoinformatics

Supervision and host laboratory

The internship student will be hosted in the CAPSID team within LORIA at the INRIA Grand Est site at Nancy. CAPSID team (https://capsid.loria.fr/) is directed by Dr. Marie-Dominique Devignes and provides a multidisciplinary and international environment for students. The student will be supervised by Dr. Yasaman Karami, chargée de recherche Inria, with expertise in understanding proteins conformational dynamics and drug design [4,5]. The team benefits from experts in Structural Bioinformatics as well as in Computer Science. The group consists of 6 permanent researchers and 4 PhD students. The group is equipped with a computational platform, MBI-DS4H (https://mbi-ds4h.loria.fr/) composed of 8 nodes and 12 GPUs, and provides technical support to the users.

The Loria center has a canteen with reduced prices for students and also provides transportation cards for students with reduced prices.

The internship is planned to start as soon as possible.

References

[1] Gheeraert A, Vuillon L, Chaloin L, Moncorgé O, Very T, Perez S, Leroux V, Chauvot de Beauchêne I, Mias-Lucquin D, Devignes MD, Rivalta I, Maigret B. Singular Interface Dynamics of the SARS-CoV-2 Delta Variant Explained with Contact Perturbation Analysis. J Chem Inf Model. 2022; 62(12):3107-3122.

[2] Karami Y, Laine E, Carbone A. Dissecting protein architecture with communication blocks and communicating segment pairs. BMC bioinformatics. 2016; 17.2: 133-148.

[3] Karami Y, Bitard-Feildel T, Laine E, Carbone A. “Infostery” analysis of short molecular dynamics simulations identifies highly sensitive residues and predicts deleterious mutations. Scientific reports 2018; 8(1): 1-18.

[4] Temmam S, Vongphayloth K, Baquero E, Munier S, Bonomi M, Regnault B, Douangboubpha B, Karami Y, et al. Bat coronaviruses related to SARS-CoV-2 and infectious for human cells. Nature. 2022; 604.7905: 330-336.

[5] Karami Y, Lopez-Castilla A, Ori A, Thomassin JL, Bardiaux B, Malliavin T, Izadi-Pruneyre N, Francetic O, Nilges M. Computational and biochemical analysis of type IV pilus dynamics and stability. Structure. 2021; 29.12: 1397-1409.