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Simulating the dynamics of viral evolution: A computer-aided study toward engineering effective vaccines

Periodic Reporting for period 1 - ENGEMED (Simulating the dynamics of viral evolution: A computer-aided study toward engineering effective vaccines)

Reporting period: 2018-11-01 to 2020-10-31

Although major advances have been made in understanding pertinent molecular and cellular phenomena, an understanding of the mechanistic principles that govern the emergence of an immune response has proven so far to be elusive. Therapeutic agents that target regions of the viral proteome wherein mutations lead to a large cost in replicative fitness, can be very effective for viral control or aborting the infection. Systematic means to derive the viral fitness landscape permits the identification of such regions. Through “ENGEMED” we describe: (i) a computational method based on statistical mechanics theory that can translate viral sequence databases into quantitative landscapes of intrinsic fitness of viral strains, containing multiple, potentially synergistic, mutations; and, (ii) a modeling work aiming at assaying a novel class of nanoparticles synthesized at the IMES of MIT to be used as carrier systems of short interfering RNAs toward the production of RNA interference–based targeted therapeutics and vaccines. To this end, it has been proved that the inferred fitness landscapes computed by means of theory developed and presented for first time by Prof. A. K. Chakraborty at the IMES of MIT can be used for in silico immunogen design. Also, molecular dynamics simulations in full atomistic detail coupled with free energy computations have been conducted to explore the binding dynamics and thermodynamics of siRNA with selected epoxide- and acrylate-derived lipopeptides, synthesized at the IMES of MIT. Objective of “ENGEMED” is the manipulation of experimental information provided by the MIT group, in close synergy with advanced computational tools developed by the researcher’s group at the Chemical Engineering of the National Technical University of Athens. Our future goal through this MSC project is to contribute to vaccines development so that they become a systematic scientific and engineering discipline harnessing deep knowledge of the human biological system.
Our results suggest that the knowledge required to achieve the goal referred above is currently missing; it can be obtained through multidisciplinary research approaches, such as the investigation of mutational vulnerabilities of pathogens, which is the task constituting the first part integrated work package of the ENGEMED’s outgoing phase at MIT. RNA interference (RNAi) is considered as a powerful method for developing new generation of therapeutics. The latter subject constitutes the second integrated work package that was accomplished during ENGEMED’s outgoing phase at MIT.

Concluding Remarks /Societal Impact

The inferred fitness landscape compares well with in vitro replicative fitness data

The inferred fitness landscapes can be used for in silico immunogen design.

Molecular dynamics simulations in atomistic detail coupled with free energy computations were performed for first time (see publication below at the American Chemical Society journal JCTC) to explore the binding dynamics and thermodynamics of siRNA with selected epoxide- and acrylate-derived lipopeptides, synthesized for first time at the IMES of MIT.

The computational binding thermodynamics of the RNA-LP complex shows a negative entropic contribution, due to increasing disorder upon complexation, as opposed to a positive enthalpic part, suggesting that the binding of lipopeptides to siRNA is an endothermic process driven predominantly by entropy.

Dissemination Activities
1. G.K. Papadopoulos, et al., J. Chem. Theory Comput. 2021, 16, 3842.
2. G.K. Papadopoulos, et al., submitted to Angewandte Chemie, Int.Ed.
3. Undergraduate Workshop on Computational Biology, held at the School of Chemical Engineering, NTUA. Academic year: 2019.
4. Interdisciplinary Postgraduate Engineering School of NTUA, Athens, 2019 – today (list of teaching staff: https://mathtechfin.math.ntua.gr/index.php/didaskontes/)
5. Participation to the European Researchers’ Night 2019, Friday 27 September 2019. Attendees: ca. 15,000 at the Historical NTUA Building, Old Center Athens.
6. Distinctive participation of the “ENGEMED” MSC project to the European Researchers’ Night 2020, Friday 27 November 2020.
7. Participation at the meeting and Workshop organized by EC at the MIT, gathering all MSC Global Fellows being at MIT, 19 – 20 February 2020, Tech Square Building 5A, Cambridge MA, USA.
8. 45th International Medical Conference, 15 – 18 May Athens, Greece 2019.
Attendees: ca. 2500.
9. 12th PanHellenic Chemical Engineering Conference, 29 – 31 May Athens, Greece 2019. Attendees: ca. 700.
10. Participation of the “ENGEMED” MSC project to the National Infrastructures for Research and Technology which provides high performance computing resources to the international scientific and research communities in order to conduct scientific research (PRACE Network), from 2018 - today.
11. http://www.chemeng.ntua.gr/dep/gkpap/projects/msc-engemed
12. https://www.Facebook.com/engemedH2020
Potential Societal Impacts
The ENGEMED’s objective: Engineering nanoparticles intended as gene therapeutics and vaccines, is of significant importance since the delivery of nucleic acids by means of properly engineered nanoparticles (NP) is considered a powerful method for developing new generation of therapeutics and vaccines against viral infections (COVI disease is a recent example), and targeted therapies (against cancers). Therefore, the task of computer-aided engineering of nanoparticles will be extended further during the incoming phase. This objective will be further enriched being motivated by the continuously developing field of gene-based therapeutics, and, in view of the novel nanoparticle systems which are produced at MIT. Thus, we intend to extend much of our efforts toward modeling NPs to test the safe and efficacious delivery of nucleic acids (e.g. siRNAs, mRNAs).

Expected Results until the End of the Project
Investigation of Stereoisomerism on the siRNA and mRNA binding with lipid components of the Nanocarrier system: Could it be serve as an efficient design parameter toward modulating the strength of the complex?
If yes, it may encourage further exploration of stereochemically pure carriers or mixtures of selected diastereomers that may help tuning biomolecular complexes to an optimum strength in order to control the interplay between complex stability, and ease of releasing the nucleic acid drugs into the cell.
Development of efficient algorithms (return's phase Work Package) toward modeling Transcription Factors (TF) to explore the formation of biomolecular condensates with the DNA. Our simulation tools (from full atomistic to coarse grain representation of selected proteins) will be utilized in order to study the interaction and free energies of the involved moieties in the DNA transcription process.
The LP-B disrupts the Watson-Crick base pairing
Molecular dynamics study depicting the LP-A upon binding to siRNA