QM-MM simulations on p53-DNA complex: a study of hot spot and rescue mutants
- PDF / 1,011,071 Bytes
- 15 Pages / 595.276 x 790.866 pts Page_size
- 56 Downloads / 173 Views
ORIGINAL PAPER
QM-MM simulations on p53-DNA complex: a study of hot spot and rescue mutants Shruti Koulgi & Archana Achalere & Neeru Sharma & Uddhavesh Sonavane & Rajendra Joshi
Received: 4 July 2013 / Accepted: 21 October 2013 / Published online: 21 November 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract p53 is a transcription factor involved in the expression of a number of downstream genes in response to genotoxic stress. It is activated through post translation modifications in normal as well as cancerous cells. However, due to mutations occurring in p53 in cancer cells it is not able to perform its function of DNA binding which leads to cell proliferation. It is found to be mutated in 50 % of the cancers. These mutations occur at a high frequency in the DNA binding region of the p53. Among the known seven hot spot cancer mutations G245S, R249S, and R273C have been studied here using quantum mechanics and molecular mechanics (QM-MM) simulations. These mutations along with their experimentally proven rescue mutations have also been included in the present work. A comparative study of these cancer mutations along with wild type and their rescue mutations has been performed. A computational measure based on the free energy changes occurring in the binding of the p53 to the DNA has been presented. A correlation between the DNA binding property and important interaction between p53 and DNA has been observed for all the mutants. The keys residues which contribute to the binding of p53 to DNA by forming crucial hydrogen bonds have also been discussed in detail. A 30 ns simulation study was analyzed to observe the local structural changes and DNA binding property of p53 in case of wild type, cancer and rescue mutants. Keywords Free energy . p53-DNA complex . QM-MM simulations . Rescue mutations
Electronic supplementary material The online version of this article (doi:10.1007/s00894-013-2042-2) contains supplementary material, which is available to authorized users. S. Koulgi : A. Achalere : N. Sharma : U. Sonavane : R. Joshi (*) Bioinformatics Group, Centre for Development of Advanced Computing (C-DAC), Pune University Campus, Pune, India 411 007 e-mail: [email protected]
Introduction The transcription factor p53 is a tumor suppressor protein which is involved in up-regulation of various genes under stress conditions such as DNA damage and many others. It normally functions in the cellular processes such as cell cycle arrest, DNA repair and apoptosis [1, 2]. On the other hand reduction or elimination of the p53 activity is characteristic of more than half of all human cancers. One of the major causes in reduction of p53 activity is associated with its mutations [3, 4]. Most of these mutations occur in the sequence-specific DNA binding core domain [4–6]. In the recent past there has been a lot of progress on cancer therapies that target p53 mutants for drug intervention of tumors [7]. p53 is a 393 residue long protein which functions as a tetramer to perform DNA binding. Each monomer interacts with the DNA thr
Data Loading...
