The C-terminal domain of measles virus nucleoprotein is an intrinsically disordered protein that could bind to the X domain (XD) of phosphoprotein P to exert its physiological function. Experiments reveal that the minimal binding unit is a 21-residue alpha-helical molecular recognition element (alpha-MORE-MeV), which adopts a fully helical conformation upon binding to XD. Due to currently limited computing power, direct simulation of this coupled folding and binding process with atomic force field in explicit solvent cannot be achieved. In this work, two advanced sampling methods, metadynamics and parallel tempering, are combined to characterize the free energy surface of this process and investigate the underlying mechanism. Starting from an unbound and partially folded state of alpha-MoRE-MeV, multiple folding and binding events are observed during the simulation and the energy landscape was well estimated. The results demonstrate that the isolated alpha-MORE-MeV resembles a molten globule and rapidly interconverts between random coil and multiple partially helical states in solution. The coupled folding and binding process occurs through the induced fit mechanism, with the residual helical conformations providing the initial binding sites. Upon binding, alpha-MORE-MeV can easily fold into helical conformation without obvious energy barriers. Two mechanisms, namely, the system tending to adopt the structure in which the free energy of isolated alpha-MORE-MeV is the minimum, and the binding energy of alpha-MoRE-MeV to its partner protein XD tending to the minimum, jointly dominate the coupled folding and binding process. With the advanced sampling approach, more IDP systems could be simulated and common mechanisms concerning the coupled folding and binding process could be investigated in the future. (C) 2016 Published by Elsevier Inc.