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FRIPRO-Fri prosjektstøtte

Mapping protein-membrane interfaces for a better description of the protein-lipid interactome

Alternative title: Kartlegging av protein-membran grenseflater for en bedre beskrivelse av protein-lipid interactome

Awarded: NOK 10.0 mill.

Project Number:

288008

Application Type:

Project Period:

2019 - 2024

Funding received from:

Location:

Proteins are Nature's building blocks but not only, they are dedicated and skilled workers, each fulfilling its own specific role. They are fairly large molecules, containing thousands of atoms. When one or several key proteins are not able to fulfill their function in the human body, this might potentially result in diseases. Although proteins are large for being molecules, they are rather small in size and are difficult to observe directly. Hence it is often handy to build molecular models, using computers, and simulate their behavior. The models are built from physics and chemistry principles, and the simulations have proven to be useful to learn more about how, for example, proteins can bind to cell membranes or calculate the forces between proteins and lipids, which are the main membrane constituents. Computers are also useful -and necessary- to collect and analyse the large amount of biological data that is already available in public databases. In this way one can for example compare many proteins and discover common traits in their amino acid composition or three-dimensional structure. In this project we focus on a particular type of proteins, which perform their function at the surface of the cells or organelles, and have the ability to stick to cell or organelles membrane of the cells for just the right amount of time to achieve their tasks there, and leave again when the job is done. These proteins are called peripheral proteins. We aim at finding out which are the forces that bring these proteins to the membrane, and how the duration of that stay is regulated by the same forces. To this aim we are following two main approaches. The first one is a top-down approach where we do statistical analysis of a large collection of peripheral proteins. The second one is a bottom-up approach where we use very accurate methods to study a small number of proteins. That allows to simulate the behaviour of a molecule in a way that models in-vitro conditions. Molecular simulations allow us to precisely calculate the forces at play between the protein and the membrane. Lessons learned with molecular simulations will be confronted to results from the top-down approach. The first and critical step in the top-down approach is collecting and curating a dataset of peripheral proteins. Based on the published literature in the field and a survey of the abundance of data in public databases, we have identified the protein families to be included in the study. We have gathered structure and sequence data for a few of them already, implemented an automated pipeline for data gathering and analysis, including a statistical framework for dataset analysis. We have identified structural patterns and particular amino acid compositions that characterise the membrane-binding regions of peripheral proteins. We have chosen short peptide models, as well as more complex proteins such as phospholipase and lipid-transfer proteins. We have run extremely long simulations using the national high-performance computers. These are giving us insights into the way the peptides and proteins recognise and insert in-between lipids at the membrane surface. Within the amino acids identified in the top-down approach there are three types that we so long have been able to follow in simulations of single proteins. We have shown why they are important for protein-membrane binding, and how they recognise particular amino acids.

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Proteins are Nature's building blocks but not only, they are dedicated and skilled workers, each fulfilling its own specific role. They are fairly large molecules, containing thousands of atoms. When one or several key proteins are not able to fulfill their function in the human body, this might potentially result in diseases. Although proteins are large for being molecules, they are rather small in size and are difficult to observe directly. Hence it is often handy to build molecular models, using computers, and simulate their behavior. The models are built from physics and chemistry principles, and molecular dynamics simulations have proven to be useful to learn more about how, for example, proteins can bind to cell membranes or calculate the forces between proteins and lipids, which are the main membrane constituents. Computers are also useful -and necessary- to collect and analyse the large amount of biological data that is already available in public databases. In this way one can for example compare many proteins and discover common traits in their amino acid composition or three-dimensional structure. In this project we focus on a particular type of proteins, which perform their function at the surface of the cells or organelles, and have the ability to stick to cell or organelles membrane of the cells for just the right amount of time to achieve their tasks there, and leave again when the job is done. We aim at finding out which are the forces that bring these proteins to the membrane, and how the duration of that stay is regulated by the same forces. To this aim we will use a combination of molecular dynamics simulations and bioinformatics analysis of publicly available data, as well as experiments in the lab using solid-phase nuclear magnetic resonance.

Funding scheme:

FRIPRO-Fri prosjektstøtte

Funding Sources