The ‘order-to-disorder’ conformational transition in CD44 protein: An umbrella sampling analysis

• The umbrella sampling simulations of the CD44 protein was performed.
• The free energy profiles accompanying the ‘order-to-disorder’ conformational transition was obtained.
• The role of Tyr161 is not limited to its attractive interaction involving Glu48 and Leu52.
• The function of Tyr161 is not definitely verified and requires further studies.

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.

The molecular modeling studies (umbrella sampling) were carried out to recover the free energy profiles corresponding to the initial steps of the ‘order-to-disorder’ conformational transition in the CD44 molecule.Figure optionsDownload high-quality image (122 K)Download as PowerPoint slide