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

Periodic Reporting for period 2 - ENGEMED (Simulating the dynamics of viral evolution: A computer-aided study toward engineering effective vaccines)

Reporting period: 2020-11-01 to 2021-10-31

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. Through ENGEMED's systematic computational means, and clinical/experimental data provided by the partner IMES of MIT, the following objectives were accomplished:
(i) A computational method based on statistical mechanics theory that can translate viral sequence databases into quantitative landscapes of intrinsic fitness of viral strains.
(ii) A modeling scheme aiming at engineering novel classes of nanoparticles, synthesized at MIT, in order to be used as carrier systems for short interfering RNAs, toward RNA interference–based targeted therapeutics and vaccines.
(iii) The development of efficient algorithms based on statistical mechanics, shed light for first time to a DNA-based enantioselective catalytic reaction, conducted at the Johns Hopkins University.
(iv) An atomistic simulation study of transcription factors (TF) upon its binding to DNA; TFs act as major regulators of gene expression and cellular differentiation. This last task seeks to address the way the TF mutations modulate the TF-DNA complex dynamics in order to assist novel therapeutic routes that target the transcriptome. The current objective will be continued after the end of the project in collaboration with MIT and a EU group at the Max Plank Inst. in Germany.
Our overall objective is the manipulation of the experimental information and computational biology-based methodology, in close synergy with advanced computational tools developed by the NTUA group of the PI of ENGEMED at the Chemical Engineering department of NTUA.
Our future goal, through, and after, this MSC project is to contribute, via in silico design, to engineering gene-based pharmaceutics and vaccines, so as computational biomedical engineering to become a systematic scientific and engineering discipline harnessing deep knowledge of the human biological system.
Concluding Remarks /Societal Impact

- The inferred fitness landscape compares well with in vitro replicative fitness data setting the basis 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 mechanism of DNA-based enantioselective catalytic reaction conducted at the ChE department of JHU, was explained for first time by means of the computational tools developed by ENGEMED (see publicatoion 2a below).
- Our overall results suggest that the knowledge required to achieve the goal referred in the summary for publication can be obtained through multidisciplinary research approaches, such as the investigation of mutational vulnerabilities of pathogens, which is the task constituting one of the first part of the work to be accomplished during the outgoing phase at MIT. RNA interference (RNAi) constitutes the second integrated work package that was accomplished during the project’s outgoing phase at MIT; RNAi is considered a powerful biomedical scheme for developing new generation of gene-based therapeutics.

Dissemination Activities
1 G.K. Papadopoulos, et al., Journal of Chemical Theory and Computation (Publ. American Chemical Society), 16, 3842, 2021
2a G.K. Papadopoulos, et al., Journal of the American Chemical Society (Publ. American Chemical Society), 2, 483, 2022
2b The above publication was selected for the JACS journal cover of February 2, 2022 (see FIG. C)
3 G.K. Papadopoulos, et al., Journal of Physical Chemistry B, (Publ. American Chemical Society); DOI received
4 G.K. Papadopoulos, et al., Annual Workshop of the American Institute of Chemical Engineers, Nov. 7-19, 2021, Boston, US
5 Graduate Workshop on Computational Biology, held at MIT, 2021
6 Undergraduate Workshop on Computational Biology, NTUA. 2019
7 Graduate Class Engineering School of NTUA, Athens, 2019 – today (list of teaching staff:
8 Researchers’ Night 2019, 27 September 2019, Historical NTUA Building, Athens
9 Distinctive participation (applicant plenary speaker) of the “ENGEMED” MSC project in the Researchers’ Night, 27 November 2020
10 Researchers' Night; 2021 and 2022, NTUA
11 Meeting-Workshop organized by EC at the MIT, gathering all MSC Global Fellows of MIT, open to to all Academic MIT Community; 19 – 22 February 2020, Boston, US
12 International Medical Conference, 15 – 18 May Athens, Greece 2019
13 47th Medical Conference, Athens, Greece, May 20 - 22, 2021
14 48th Medical Conference, Athens, Greece, May 12 - 14, 2022
15 12th Chemical Engineering Conference, 29 – 31 May Athens, 2019
16 13th Chemical Engineering Conference Patras, June 2 - 4, 2022
17 Participation of the “ENGEMED” 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.
18 Official Publications Depository:
19 Facebook:
Potential Societal Impacts

- The overall 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).
- We must stress that via ENGEMED, we started dealing with the RNA technology - by testing efficient nanocarrier systems for short interfering RNA molecules - well before the RNA technology became a "sine qua non" for the humanity as a result of the COVID pandemic (see publication 1 below).
- Development of efficient algorithms (return phase) toward modeling transcription factors (TF) to explore the formation of biomolecular condensates with the DNA. Our simulation tools (full atomistic to coarse grain modeling) are currently utilized to study the interaction and free energies of the involved moieties in the DNA transcription process. The work will be conducted in collaboration with experiments from the EU Max Plank Inst.
The LP-B disrupts the Watson-Crick base pairing
Molecular dynamics study depicting the LP-A upon binding to siRNA