Human myoglobin: two isoforms that differ at single residue. Their different dynamics suggest distinct and complementary role

In Human up to five different myoglobin isoforms are expressed. Iso-I (∼75-80%) and iso-II (∼15-20%) are the more expressed ones and differ only at the 54th position, K54 and E54 respectively. It has been reported that myoglobin concentration in muscles is higher for high-altitude natives than sea-level populations, and that only iso-II is over-expressed among the myoglobin isoforms. This over-expression is thought to be one of the evolutive adaptation to the high-altitude hypoxic environment. Since it is widely accepted that myoglobin is not only an oxygen storage/deliver system, iso-II over expression has been related to other functions such as NO scavenger and/or nitrite reductase. In this work Molecular Dynamics simulations were applied to study the dynamics of 54K and 54E human myoglobins. Statistical analysis of internal cavities and their interconnections helped to highlight and compare the intrinsic dynamic behavior of these two proteins. Furthermore, the role of the solvent in the mutation proximity has been investigated and it was found that water molecules can quasi-allosterically modulate the dynamics of myoglobin distal region. Important differences have been found especially at the histidine gate, even if the two myoglobin isoforms differ at only one residue that, indeed, is not located at the gate itself. These differences suggest that the two more expressed human myoglobins might have a distinct and complementary role. This would well fit the literature scenario where NO scavenging is though to be important at normoxic condition to retain mitochondrial respiration efficacy, while nitrite reduction is believed to be crucial under hypoxic stress. NO release by myoglobin would decrease mitochondrial oxygen consumption preserving the optimal O2 gradient across the cell but also ensuring sufficient ATP synthesis