Networks top down; Signal transduction in and between proteins

Macromolecular interactions such as protein-protein interactions are crucial for most biological processes. Tens of thousands of proteins and other macromolecules are expressed in a typical cell, mediating thousands of physical interactions at a given moment, either to form molecular machines or to participate in various regulatory processes. It is essential to understand how these interactions are organized and how signals can be transmitted between the macromolecules, because failure in interaction and signalling could lead to diseases or even death. In the research project I propose, the network and dynamics of interactions in and between proteins are investigated by computational methods to elucidate possible mechanisms of intra and intermolecular signal transmission. I want to determine how signals can be propagated within and between proteins. To do so, temporal and spatial changes in the interaction network will be analysed in detail. This analysis will help to develop possible models for signal transmission in and between macromolecules. It will improve our understanding of how living organism can process and store information, as well as make decisions which is crucial for their survival. Furthermore, it will increase our capability to intervene specifically in biological processes and prevent failures in signal transmission which could be linked to disease.

Network analysis has been applied widely, providing a unifying language to describe interaction patterns in various systems ranging from technological to social interactions. Recently, it has also been used to analyse biological systems, but so far molecular networks have only been analysed statically. Here, the dynamics of intra and intermolecular interaction networks are studied to elucidate the mechanisms of signal transduction.
First, NMR relaxation data will be used in restrained molecular dynamics simulations to study the changes in protein dynamics upon complex formation. The detailed analysis of these changes will allow us to propose molecular mechanism by which signals, triggered upon binding, can be transmitted across a protein or protein-complex structure. Then, the effect of this signal on other proteins, i.e., their expression level and changes in their interaction network will be analysed. It will be investigated how the possible effect of the signal depends on the moment in the cell cycle it was triggered, because the interaction network of proteins varies significantly during the cell cycle. I will track down pathways which connect distal parts of the interaction network in the cell most effectively. Moreover, interaction properties of proteins involved in the signalling network will be studied. The detailed analysis of both intra and intermolecular interaction networks and their changes in time will help to understand how macromolecules can process information and make decisions. Understanding the mechanisms of communication in and between macromolecules will allow us to steer biological processes more effectively and intervene in cases of interaction failure that could ultimately lead to disease.