Development of new anti-cancer peptides from conformational energy analysis of the oncogenic ras-p21 protein and its complexes with target proteins

Frontiers in Bioscience : a Journal and Virtual Library
Matthew R Pincus

Abstract

We have employed a computational approach to design peptides, from known oncogenic proteins, that inhibit tumor growth. This approach has been applied to the ras-p21 protein that becomes oncogenic when single amino acid substitutions occur at critical positions in its polypeptide chain, such as at Gly 12 and Gln 61. In this approach, using two sampling methods, molecular dynamics and the electrostatically driven Monte Carlo (EDMC) method, we have computed the average structures of wild-type and oncogenic forms of ras-p21 alone and bound to a number of its target proteins, such as the ras-binding domain (RBD) of raf, guanine nucleotide exchange protein (GAP) and SOS guanine nucleotide exchange protein (GAP). By superimposing the average structures of the oncogenic forms on those of their wild-type counterparts, we have identified a number of domains that change conformation. These domains are potential effector domains that are involved uniquely in oncogenic ras-p21 signaling. We have therefore synthesized peptides corresponding to these domains and tested them in Xenopus laevis oocytes for their abilities to inhibit oncogenic ras-p21 selectively. Using this approach, we have identified three peptides from ras-p21 and one peptid...Continue Reading

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