The 'order-to-disorder' conformational transition in CD44 protein: an umbrella sampling analysis

The molecule of CD44, a membrane protein being the major cell surface receptor for hyaluronan, is postulated to undergo the conformational rearrangement called the 'order-to-disorder' transition. The experimental studies suggest that the Tyr161 residue is crucial for maintaining the equilibrium between the 'ordered' (O) and 'partially disordered' (PD) forms of CD44. The molecular modeling study based on the umbrella sampling protocol was carried out separately for the wild-type CD44 and Tyr161Ala mutant in order to gain more insight into the molecular mechanism of the O-PD transition and to clarify the role of the Tyr161 amino acid residue. The calculated free energy profiles associated with the initial stages of the O-PD conformational transition allow to identify the crucial steps of this process and their molecular details. The differences between the wild-type CD44 and the Tyr161Ala mutant are very insignificant which allows for speculating that, surprisingly, the role of Tyr161 in the O-PD transition is not connected with disrupting the attractive Glu48-Tyr161 and Leu52-Tyr161 interactions but with other types of (unknown yet) interactions located outside the β7-β8 loop or with the existence of the PD-like structure in which the terminal lobe remains located under the β7-β8 loop.