Title:Computational Investigation on the MDM2-Idasanutlin Interaction Using the Potential of Mean Force Method
Volume: 15
Issue: 3
Author(s): Pundarikaksha Das and Venkata Satish Kumar Mattaparthi*
Affiliation:
- Molecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur-784 028, Assam,India
Keywords:
Potential of mean force, idasanutlin, binding free energy, per residue energy decomposition, MDM2, root mean square deviation.
Abstract: Background: The Murine Double Minute 2 (MDM2) protein is a well-studied primary
negative regulator of the tumor suppressor p53 molecule. Therefore, nowadays many research
studies have focused on the inhibition of MDM2 with potent inhibitors. Idasanutlin (RG7388) is a
well-studied small molecule, the antagonist of MDM2 with potential antineoplastic activity. Nevertheless,
the highly significant information pertaining to the free energy profile, intermediates, and
the association of receptor and ligand components in the MDM2-idasanutlin complex remains unclear.
Objective: To study the free energy profile of the MDM2-idasanutlin complex in terms of the Potential
of Mean Force (PMF) method.
Methods: We have used the PMF method coupled with umbrella sampling simulations to generate
the free energy profile for the association of N-Terminal Domain (NTD) of MDM2 and idasanutlin
along with a specific reaction coordinate for identifying transition states, intermediates as well as
the relative stabilities of the endpoints. We also have determined the binding characteristics and interacting
residues at the interface of the MDM2-idasanutlin complex from the Binding Free Energy
(BFE) and Per Residue Energy Decomposition (PRED) analyses.
Results: The PMF minima for the MDM2-idasanutlin complex was observed at a center of mass
(CoM) distance of separation of 11 Å with dissociation energy of 17.5 kcal mol-1. As a function of
the distance of separation of MDM2 from idasanutlin, we also studied the conformational dynamics
as well as stability of the NTD of MDM2. We found that there is indeed a high binding affinity
between MDM2 and idasanutlin (ΔGbinding = -3.19 kcal mol-1). We found that in MDM2, the residues
MET54, VAL67, and LEU58 provide the highest energy input for the interaction between
MDM2 and idasanutlin.
Conclusion: Our results in this study illustrate the significant structural and binding features of the
MDM2-idasanutlin complex that may be useful in the development of potent inhibitors of MDM2.
