Multiscale Simulations of disease-related biomolecular systems
Title: Multiscale Simulations of disease-related biomolecular systems
DNr: NAISS 2023/5-27
Project Type: NAISS Medium Compute
Principal Investigator: Laura Orellana <>
Affiliation: Karolinska Institutet
Duration: 2023-02-01 – 2023-10-01
Classification: 10603 10203 10601


Proteins conform the ultimate machinery of Life, executing all processes that sustain living organisms – from metabolic pathways to neurotransmission. Far from being static, at physiological temperatures, proteins vibrate and cycle between different states or conformers, sensing external signals: in the same way that primary sequences fold into 3D-sructures, each shape encodes intrinsic functional motions of such relevance for life that remain untouched from bacteria to humans. Nevertheless, despite its central role in Life, understanding the tight link between protein structure, motion and function i.e. the exploration of protein conformational landscapes, it is still a challenging task. To overcome these limitations, our research integrates coarse-grained path-sampling, ensemble-level analysis and atomistic simulations of “hot” mutations related to human diseases [1-2]. This project aims to apply this multiscale approach to dissect the essential motions orchestrating function in highly complex systems, in order to obtain functional insights and validate them [3-4] through our collaborations as well as in house experiments. Among others, we will simulate: 1) The conformational dynamics of the full-length EGF-Receptor, a key oncogene for which we are performing cryo-EM studies in collaboration with Black Diamond Therapeutics (NY, USA), based on our previous work published in PNAS and Cancer Cell. Our preliminary simulations of this huge system have revealed its dynamics in solution, and will be critical to understand its activation mechanisms and interpret ground-breaking but challenging cryo-EM data- 2) Mutations in multiple proteins related to Skeletal Dysplasias and other rare diseases, for which we have e.g. identified novel mechanisms involving highly specific protein-rRNA interactions. This work is done in collaboration with clinical geneticists Prof. Grigelioninene and Prof. Fulya Talyan (KI-MMK), and has been funded by a KI Interdisciplinary Incubator Grant. 3) Drug interactions and folding/oligomerization of p53, a tumor repressor gene, for which we collaborate with Prof. Klas Wiman and Prof. Joanna Zawacka-Pankau 4) Dynamics and interactions of leukotriene pathway enzymes, in collaboration with Prof. Jesper Haeggstrom Apart of above highly relevant systems, our group works developing sampling algorithms, benchmarking and testing them for representative proteins, a task that requires extensive computational power. [1] L. Orellana, O. Yoluk, O. Carrillo, et al. Nat. Communications, 2016, 7: 12575 [2] L. Orellana, Frontiers in Molecular Biosciences, 2019, 6, 117. [3] A.R. Mhashal, O. Yoluk, L. Orellana L Frontiers in Molecular Biosciences, 2022, 9, 890851 [4] L. Orellana, Thorne AH, Lema R, et al Proceedings of the National Academy of Sciences of the United States of America, 2019, 116