Molecular Dynamics on Stapled Peptide - Computational Drug Design скачать в хорошем качестве

Molecular Dynamics on Stapled Peptide - Computational Drug Design

Probing the α-helical structural stability of stapled p53 peptides using replica exchange molecular dynamics. Zoujun Guo, Udayan Mohanty, Justin Noehre, Tomi Sawyer, Woody Sherman, and Goran Krilov. Background Biology: Mdm2 is a negative regulator of the p53 tumor suppressor protein. A helical portion of p53 binds to mdm2 and recent studies have shown that the helical propensity of peptide fragments as measured by circular dichroism (CD) is correlated with inhibitory mdm2 activity. A new synthetic chemistry technology to staple peptides is a way to increase the helical nature of a peptide. The Aim: Stapled peptides have been shown to have increased helical characteristics in solution and also increase binding activity to mdm2. Predicting the effect of a staple on helical stability could aid in the understanding and design of therapeutic agents. We aim to see if the helical stabilizing properties of the staple can be reproduced using computer simulations. Simulation Details: Replica exchange molecular dynamics (REMD) was run on a wild type p53 peptide and a stapled variant. A total of 64 replicas were run across 64 processors with a temperature range of 300-600 K, for a cumulative simulation time of 320 ns for each peptide. Comments: Stapled peptide has increased helical stability. The staple is shown in cyan color. Wild type (unstapled) peptide has decreased helical stability. Residues Leu, Trp and Phe are critical for high affinity peptide binding. They are highlighted in CPK representation. Even after 5 ns of REMD with 64 replicas ranging from 300-600 K, the stapled peptide maintains its helical structure. Music: Another Way [Radio Mix] - Paul Van Dyk Software: Schrodinger Suite 2009 and PyMOL (www.schrodinger.com) Noeris Salam