Research team Laura Orellana: Protein Dynamics and Mutation Lab

This new research team is lead by Laura Orellana. Our research aims to understand protein function and disease mechanisms through conformational dynamics and evolution.

Mutant EGFR intermediate conformation exposing the epitope for the antibody ABT-806 (purple) as seen in Molecular Dynamics simulations
Mutant EGFR intermediate conformation exposing the epitope for the antibody ABT-806 (purple) as seen in Molecular Dynamics simulations (Orellana et al., PNAS 2019). Credit: Dr Laura Orellana

Research Description

How a single mutation can disrupt protein function and propagate throughout scales, from cells to tissues and the whole organism causing diseases like cancer? How the change of just a few atoms in an oncogene can trigger the formation of a tumor? Howis the sequence of a protein related to its shape and function? We aim to answer these fundamental questions by exploring the molecular basis of mendelian diseases and cancer at the deepest level, in terms of protein structures and their motions at the atomic scale. In the same way as animal shapes are selected by evolution to fly, run or swim, each protein fold has been evolutionarily selected to perform certain motions, the so-called “conformational-changes”, which dictate biological function. In cancer cells, proteins also mutate and quickly evolve their “phenotypes” - their conformational dynamics and resulting cellular function - in order to adapt to their environment and promote oncogenic growth. To reveal the key dynamic information contained in cancer mutation patterns, we develop simulation methods (Front.Mol.Biosciences, 2019; Nat.Comms, 2016) and servers (Bioinformatics, 2019) and integrate them with structural determination techniques (SAXS, cryoEM), in vitro and in vivo experiments. Using this interdisciplinary approach, we discovered that EGFR mutations in brain tumors converge to acquire a similar conformation, which is antagonistic from mutations in lung cancer and respond to different drugs. Our mechanistic insights set a rational basis for synergistic drug combinations that trap this glioblastoma-specific EGFR conformation, triggering tumor regression in animal tumor models (PNAS, 2019; Cancer Cell, 2018). Our goal is to go beyond conventional oncogenes like EGFR and perform a complete conformational profiling of tumors, which will be essential to identify, group and rationally target evolutionarily selected mutations with conformation-specific drugs. We are also interested in mendelian disease mutational patterns, which can reveal essential aspects of protein function and we have shown unexpectedly overlap with mutations found in human tumors (Front.Mol.Biosciences, 2022).

On a broader view, we believe that understanding biomolecular dynamics, protein-protein interactions and folding, and their perturbations in human diseases is essential to connect the structural scale with higher-level observations in molecular biology and medicine and push the boundaries of biophysical research and our understanding of life mechanisms. Apart of deriving testable predictions from simulations, we have experience helping to rationalize experimental data at the structure/ dynamics- level (Nat.Comms., 2021; EMBO Journal; Nature, 2020;  Cancer Cell, 2019) and are always interested to hear about potential collaborations.

More information on our research may be found here.

Group members

Dr. Laura Orellana, Assistant Professor/Principal Investigator
Dr. Anil Mhashal, Postdoctoral Researcher
Dr. Sorbhi Rathore, Postdoctoral Researcher
Dr. Agustí Emperador, Affiliated to research
Dr. Johan Gustavsson, Consultant/external personnel

MSc thesis
Knut-Rasmus Bergendahl, M.Sc. Student Computer Sciences (KTH, 2021)
Gustav Lind, M.Sc. Student Engineering Physics (Uppsala University, 2021)

Available positions

We are an inter-disciplinary group at the crossroads of computational biophysics & structural biology to generate new insights on protein function and malfunction to be tested in vitro and in vivo. If you are interested to join or just curious to know more about our research, please contact Laura Orellana

Press releases

At the molecular level, cancer mutations echo Darwin's observations

Researchers discover the mechanism of action of an antitumor drug used for the treatment of glioblastoma

Ludwig-developed candidate drug may be effective against broader class of brain cancers

A minimalist theory to predict protein movements

De förutspår proteiners blixtsnabba rörelser

Projects and Research Lines

We develop algorithms to predict protein conformational changes and the impact of mutations on them, focusing specially on cancer:

Computational methods to study conformational changes

1) Computational multiscale methods to study protein conformational changes:

  • Coarse-grained & atomistic simulation methods: Normal Mode Analysis, Elastic Networks, Langevin Dynamics, classical Molecular Dynamics, Principal Component & Network Analysis of structural ensembles, machine learning, sampling algorithms.
  • In silico mutational screening: Development of algorithms and tools to identify “dynamically hot” mutations shifting protein conformation.

2) Protein evolution, cancer mutations and conformational dynamics:

  • Rationalization of mutational patterns for known oncogenes: conformational convergence in Tyrosine Kinase Receptors (EGFR)
  • Discovery of new cancer drivers & biomarkers including house-keeping and tissue-specific proteins

Servers: eBDIMS server

Selected Publications

Exploring the conformational impact of novel glycine receptor mutations through coarse-grained and atomistic simulations
Mhashal A.R., Yoluk O., Orellana L.
Frontiers in Biomolecular Sciences, 2022 (Accepted)

Large-Scale Conformational Changes and Protein Function: Breaking the in silico Barrier.
Orellana L
Front Mol Biosci 2019 ;6():117

Convergence of EGFR glioblastoma mutations: evolution and allostery rationalizing targeted therapy.
Orellana L
Mol Cell Oncol 2019 ;6(5):e1630798

Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope.
Orellana L, Thorne AH, Lema R, Gustavsson J, Parisian AD, Hospital A, et al
Proc Natl Acad Sci U S A 2019 05;116(20):10009-10018

Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development.
Binder ZA, Thorne AH, Bakas S, Wileyto EP, Bilello M, Akbari H, et al
Cancer Cell 2018 07;34(1):163-177.e7

Prediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations.
Orellana L, Yoluk O, Carrillo O, Orozco M, Lindahl E
Nat Commun 2016 08;7():12575

Book Chapters

Computational Techniques to Study Protein Dynamics and Conformation 

Orellana L,* Mhashal A. & Emperador A. (2022).

Advances in Protein Molecular and Structural Biology Methods. Eds. Tripathi T & Dubey V. Elsevier, USA (In Press). [ISBN: 978-032-39-0264-9].

Recent Collaborations

Crystal structures of human MGST2 reveal synchronized conformational changes regulating catalysis.
Thulasingam M, Orellana L, Nji E, Ahmad S, Rinaldo-Matthis A, Haeggström JZ
Nat Commun 2021 03;12(1):1728

Structure and lipid-mediated remodeling mechanism of the Na+/H+ exchanger NHA2
Matsuoka R, Fudim R, Jung S, Zhang C, Bazzone A, Chatzikyriakidou Y, Nomura N, Iwata S, Orellana L, Bernstein O., Drew D.
bioRxiv (2021)

Funding

Links

External Lab Website