CaSToRC, the HPC National Competence Centre,
 invites you to the EuroCC and SimEA Online Seminar Series

Abstract

Molecular simulations have been instrumental in identifying the structure-function relationships of biomolecules at the atomic level as well as providing a means for structure-based drug discovery, thereby explaining and guiding experimental findings. The increase in computational power, new physics and machine-learning-based algorithms are significantly driving the boost in the field and give access to addressing biomolecular phenomena of increasing length and timescales. In this talk, he will discuss examples where, using state-of-the-art integrative structural biology methods that inject Cryo-EM experimental data into the simulation, accurate protein-functional dynamics of the SARS-CoV-2 spike protein at an atomistic level are revealed. In this way, the following is achieved: a) reveal virus vulnerabilities by identifying cryptic binding sites exposed during the S protein conformational transition related to the recognition to the host cell [1] and b) provide with the molecular motion and energetics of protein-antibody complexes which enables to suggest mutations that increase the spike-antibody affinity [2]. These predictions are validated in further CryoEM experiments. In this talk, he will also highlight Cryo-EM/simulation-based structural dynamics-function relationships of a tau-microtubule complex implicated in AD [3].

Bibliography:

1. Brotzakis, Z. F.; Lohr, T.; Vendruscolo, M. Determination of intermediate state structures in the opening pathway of SARS-CoV-2 spike using cryo-electron microscopy. Chem. Sci. 2021, 12, 9168
2. Huo et al. (unpublished) 2022
3. Brotzakis, Z. F., et al. A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms. ACS Cent. Sci. 2021,7 (12), 1986-1995

About the Speaker

Zacharias Faidon Brotzakis is currently a FEBS individual Post-Doctoral fellow in the group of Michele Vendruscolo at the Centre of Misfolding Diseases of the University of Cambridge. In his work, he develops enhanced sampling molecular dynamics and integrative structural biology methods that combine CryoEM/NMR/Rate-constant experimental data with atomistic simulations for determining structural ensembles and force-field optimization. Such integrative methods unveil control and diagnose disease like Alzheimers Disease, SARS-Cov2, Type II diabetes. He mastered enhanced-sampling molecular dynamics as a post-doc in the Parrinello group at ETHZ and USI and during his PhD in the group of Peter Bolhuis in the University of Amsterdam. He started his academic career with his master’s thesis in polymer dynamics in the D.N. Theodorou group.

Download the Sumer 2022 Online EuroCC & SimEA Seminar Series Programme here.

The EuroCC project has received funding from the European Union’s Horizon 2020 research and innovation programme grant agreement No. 951732

The SimEA project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 810660

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