Mixed-Gen Season 3 – Session 7: Computational methods in biophysics for applications to drug discovery
Location: On-line, hosted by CECAM-HQ
The Mixed-Gen on-line series is aimed mainly at PhD students and researchers in their first post-doc. Our goal is to continue providing a venue for these young scientists to share their work, get expert feedback and have an opportunity to strengthen scientific relations within the CECAM community and beyond.
Sessions consist of two parts. In the first, publicly available on Zoom, an experienced speaker and two/three young scientists present talks. In the second, accessible only to registered participants, posters are presented in a GatherTown room.
More detailed information on the program will appear on this page closer to the date of the event.
Links for the session:
To register use the Participate tab on this page
If you do not have a CECAM account register by clicking here...and welcome to CECAM!
Submission of posters
(Please note that - at least for the time being - we shall accept posters only from PhD students or researchers in their first two post-docs)
Register for the session as described above.
After your application is accepted, you will be able to submit a poster. In the CECAM page for this event, go to “My participation” tab and click on “Add a poster”, providing title and abstract following the recommended format. On the same form you can upload your poster file in png or jpg as soon as it is ready. These formats are strict to enable showing of the poster in the Gather session. If the poster file is not ready at the moment of submitting your abstract, you can upload it later by editing your submission (Go to “My participation” tab and click three vertical dots on “Actions” column on table “My posters”). Please upload your poster as soon as possible to enable a decision from the selection committee - see below.
Please note that posters will be visible in the Gather room associated with this session until the end of the series (June 2023) unless otherwise requested.
DEADLINE FOR SUBMISSION: TEN DAYS BEFORE THE EVENT
Selection of posters
Posters will be selected by the event organisers with the support of our main speaker and experts who will take part in the poster session.
Selection of the talks by PhD or first year postdocs
These contributions, to be broadcasted in the Zoom webinar in the first part of the event, will be selected, after a preliminary screening by the organisers, the main speaker and guest experts, from the posters selected for the Gather session. Please tick “No” to the question “Upgrade to talk?” in your application if you DO NOT WANT your poster to be considered for upgrade to a talk.
THE DECISION ON THE POSTER AND THE OUTCOME OF THE SELECTION OF THE TALKS WILL BE COMMUNICATED AT THE LATEST FOUR DAYS BEFORE THE EVENT
POSTER SUBMISSIONS BEYOND THIS DEADLINE WILL BE ACCEPTED BUT NOT CONSIDERED FOR UPGRADE TO TALK. SUBMISSION WILL BE DEFINITELY CLOSED FOUR DAYS BEFORE THE EVENT.
SESSION 7. Title and abstract of talks
In Situ Dynamics Reveal Unseen Vulnerabilities of Viral Glycoproteins
Rommie Amaro , University of California, San Diego
Viral glycoproteins are important targets for vaccine and drug design. I will discuss our efforts to provide never-before-seen views of these amazing molecular machines, for both SARS-CoV-2 and influenza. For the latter, we investigated the dynamics of influenza glycoproteins in a crowded protein environment through mesoscale all-atom molecular dynamics simulations. Our simulations reveal and kinetically characterize three large-scale molecular motions of influenza glycoproteins, which expose epitopes that are otherwise hidden in static experimental structures. I will also discuss how we are using advanced simulation methods in structure-based immunogen design efforts. Our work highlights the advantages of exploring and characterizing in situ dynamics of glycosylated proteins in their native, crowded environments.
The role of heparin in spike SARS-CoV-2 infection: from a model for heparan sulfates to a starting structure for antivirals
Giulia Paiardi, Heidelberg University
Despite clinical success with anti-spike vaccines, the emergence of new SARS-CoV-2 variants highlights the necessity for a deeper understanding of the infection mechanisms and the development of broad-acting therapeutics that can reduce viral burden.
SARS-CoV-2 infection is driven by the interaction of the viral spike glycoprotein with the host cell angiotensin-converting enzyme 2 (ACE2) receptor and heparan sulfate (HS) proteoglycans, co-receptors that are indispensable for SARS-CoV-2 infection [1,2]. Experimental data indicate that the HS-analog heparin acts as an antiviral agent against SARS- CoV-2 by binding the viral spike glycoprotein . We previously revealed that long basic grooves on the spike accommodate heparin which, in turn, exerts its antiviral effect by direct and allosteric mechanisms . Based on these results, we are tackling two open mechanisms.
(i) The role of HS as co-receptors for spike infection is not yet fully understood. To investigate this mechanism, we carried out over 10us of conventional MD followed by tauRAMD simulation to systems of the spike glycoprotein homotrimer bound to ACE2 in the presence of zero to three heparin chains. Our data indicate that N-glycans and heparin stabilize the protein-protein interaction while affecting the ACE2 dynamics. Direct crosstalk between heparin and ACE2 N-glycans is identified. These mechanisms contribute to the understanding of the spike SARS-COV-2 infection mechanism.
(ii) The anticoagulant effect of heparin hinders its application as an antiviral to early-stage COVID-19 patients. For this purpose, we aimed to design heparin derivatives with antiviral but without anticoagulant activity by combining computational studies with biochemical and cellular inhibition assays. Our results suggest that N-O-sulphated and O-sulphated heparin derivatives exhibit higher antiviral activity than heparin, due to greater hindrance of ACE2 binding to spike. These results support the therapeutic potential of these heparin analogs.
 M. Hoffmann, H. Kleine-Weber, S. Schroeder, N. Krüger, T. Herrler, S. Erichsen, T. Schiergens, G. Herrler, N. Wu, A. Nitsche, M. Müller, C. Drosten, S. Pöhlmann, Cell, 181, 271-280.e8 (2020)
 T. Clausen, D. Sandoval, C. Spliid, J. Pihl, H. Perrett, C. Painter, A. Narayanan, S. Majowicz, E. Kwong, R. McVicar, B. Thacker, C. Glass, Z. Yang, J. Torres, G. Golden, P. Bartels, R. Porell, A. Garretson, L. Laubach, J. Feldman, X. Yin, Y. Pu, B. Hauser, T. Caradonna, B. Kellman, C. Martino, P. Gordts, S. Chanda, A. Schmidt, K. Godula, S. Leibel, J. Jose, K. Corbett, A. Ward, A. Carlin, J. Esko, Cell, 183, 1043-1057.e15 (2020)
 G. Paiardi, S. Richter, P. Oreste, C. Urbinati, M. Rusnati, R. Wade, Journal of Biological Chemistry, 298, 101507 (2022)
Using molecular simulations towards RNA targeting with small molecule drugs
Mattia Bernetti, Istituto Italiano di Tecnologia (IIT)
A large fraction of the transcribed RNA from the human genome is not translated into proteins, and it is nowadays clear that non-coding RNA molecules can play many functional roles. As such, they can also be involved in pathological conditions, opening the way to possibilities for therapeutic strategies, including the design of small molecule drugs able to bind and modulate the activity of RNA molecules to achieve a therapeutic effect.1 Computational methods such as molecular dynamics (MD) simulations and molecular docking have become established tools in modern drug discovery,2 but they have historically been employed to target proteins. Extending these established procedures to RNA targets poses several challenges, including the high flexibility and complex structural dynamics that they typically display.3 Indeed, RNAs are usually seen as ensembles of conformations, more than a single prevalent one. Thus, reconstructing reliable structural ensembles describing the conformational dynamics of RNA molecules is of great importance.
Within this context, I will first show a successful example of reconstructing the conformational ensemble of a biologically relevant RNA molecule, namely the GTPase-Associated Center RNA.4 Specifically, herein the goal was achieved by using a combination of small-angle X-ray scattering (SAXS) experimental data and enhanced sampling MD simulations. Subsequently, I will discuss how this general framework can be leveraged of towards a drug discovery perspective. In particular, the reconstructed ensemble for an RNA target can be used to take into account the RNA flexibility, in an ensemble-docking spirit.3 In practice, the molecular docking exercise is repeated on each conformation included in the ensemble of the RNA target. In this respect, I will show our advances towards a pharmaceutically relevant RNA molecules, namely the Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) RNA. By identifying an ensemble of conformations of this RNA, potential binding sites, and the use of docking/virtual screening procedures, our ultimate aim is to identify promising binders able to modulate its activity.
K. Warner, C. Hajdin, K. Weeks, Nat. Rev. Drug. Discov., 17, 547-558 (2018)
M. De Vivo, M. Masetti, G. Bottegoni, A. Cavalli, J. Med. Chem., 59, 4035-4061 (2016)
M. Bernetti, R. Aguti, S. Bosio, M. Recanatini, M. Masetti, A. Cavalli, QRB Discovery, 3, e22 (2022)
M. Bernetti, K. Hall, G. Bussi, Nucleic Acids Research, 49, e84-e84 (2021)
Ignacio Pagonabarraga (University of Barcelona) - Organiser
Sara Bonella (CECAM HQ) - Organiser
Andrea Cavalli (CECAM HQ) - Organiser