Researchers have revealed vital information about haemoglobin, and opened up the possibility to optimise its function by modelling its role in oxygen transportation at atomic level.
The transport of oxygen in blood is undertaken by haemoglobin, the largest component of red blood cells. This protein collects oxygen in respiratory organs, mainly in the lungs, and releases it in tissues in order to generate the energy necessary for cell survival. Haemoglobin is one of the most refined proteins because its evolution and small mutations in its structure can produce anaemia and other severe pathologies.
The investigation led by Víctor Guallar, ICREA researcher with the Life Sciences department of the Barcelona Supecomputing Center (BSC) and group leader of the Joint Computational Biology Programme between the Institute for Research in Biomedicine (IRB Barcelona) and the BSC, has allowed the definition at atomic level of the mechanism that regulates the exchange of lung oxygen to haemoglobin and from haemoglobin to tissue.
Studies have shown that haemoglobin uses mechanisms of co-operativity to optimise its function; that is to say, to collect the greatest amount of oxygen possible in the lungs and release it in tissues. These mechanisms of co-operativity are related to changes in the structure of the haemoglobin protein.
However, due to the complexity of the system, until now it has not been possible to determine the microscopic mechanisms that guide this process. Consequently, this lack of information has been a serious limitation in drug design and the development of artificial forms that are more effective than the protein.
Víctor Guallar explains, "This study has provided detailed knowledge of the mechanisms that regulate the affinity of haemoglobin, which is crucial to understand, for example, the effects caused by mutations on its structure. Thus, we have obtained basic data on the relation between mutation and disease, which will allow the development of more specific treatments."
Using sophisticated atomic calculation techniques, which combine quantum and classical mechanics, Guallar's team has determined how, against what was commonly accepted, the affinity for oxygen appears to be controlled by interactions that are relatively distant from the active centre of the protein and that are directly involved in the structural changes responsible for cooperativity.
Raúl Alcantara, first author of the study and a member of Guallar's group points out that "having access to the enormous calculation capacity of the MaresNostrum supercomputer allows more precise simulations, which are closer to what happens in real life".
According to the researchers, the results of the study open up vast possibilities for the engineering of this crucial protein. Having identified the factors that regulate the affinity of haemoglobin, alterations of its structure can now be designed.
Likewise, they add, the microscopic knowledge about the mechanisms of action of haemoglobin will improve our understanding of the effects of diverse mutations of this protein.
The results of the study are published in the journal Proceedings of the National Academy of Sciences.