Materials Science MS Defense: Developing MELD-accelerated Molecular Dynamics Protocols to Simulate the Binding of the P53-Derived Ligand to the MDM-2, X Protein
Materials Science MS Defense
Developing MELD-accelerated Molecular Dynamics Protocols to Simulate the Binding of the P53-Derived Ligand to the MDM-2, X Protein
Maria Ciko
Materials Science and Engineering MS Candidate
Rochester Institute of Technology
Abstract:
In this study, we explore complex formation via protein-ligand binding affinities, a valuable resource in disrupting the interactions that enable cancer growth in the context of drug discovery and structure-based design. Proteins have numerous degrees of freedom of internal and relative motion that can be captured by Molecular Dynamics (MD), though at a high computational cost. MELD, or Modeling Employing Limited Data, is a probabilistic approach using Bayesian integration of external information that locates the most frequent, low energy conformations, accelerating the process, and facilitates flexibility in protein-peptide interactions. In a study conducted by Morrone, MELD demonstrated correct outcomes in competitive simulations across nine P53-MDM complexes containing a peptide with a distinctive mutation. Our hypothesis is that we can effectively compute the relative binding affinities in a way that minimizes ligands’ steric hindrance and mitigates the effect of slowed diffusion on simulation convergence time. After confirming the stability of the docked systems using RMSD values, we developed efficient MELD protocols that are in reasonable accord with Morrone’s results with minimal computational effort.
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