Protein point mutations

Ki-ras Lung, pancreas, and colon GTP binding protein Point mutation... 

How can we apply molecular dynamics simulations practically. This section gives a brief outline of a typical MD scenario. Imagine that you are interested in the response of a protein to changes in the amino add sequence, i.e., to point mutations. In this case, it is appropriate to divide the analysis into a static and a dynamic part. What we need first is a reference system, because it is advisable to base the interpretation of the calculated data on changes compared with other simulations. By taking this relative point of view, one hopes that possible errors introduced due to the assumptions and simplifications within the potential energy function may cancel out. All kinds of simulations, analyses, etc., should always be carried out for the reference and the model systems, applying the same simulation protocols. 

In Figure 7b, the data are plotted as AG yielding a linear function. Extrapolation to 2ero denaturant provides a quantitative estimate of the intrinsic stability of the protein, AG, which in principle is the free energy of unfolding for the protein in the absence of denaturant. Comparison of the AG values between mutant and wild-type proteins provides a quantitative means of assessing the effects of point mutations on the stability of a protein. 

Equations (5)-(8) assume that the energy functions (7 and Ub operate on the same conformation space i.e., A and B must have the same number N of degrees of freedom. In practice, this almost always implies that A and B have the same number of atoms or particles. Most biochemical changes of interest (e.g., point mutations of a protein) do not obey this requirement, but they can often be made to do so artificially through the use of dummy atoms (see below). 

V De Filippis, C Sander, G Vriend. Pi edictmg local structural changes that result from point mutations. Protein Eng 7 1203-1208, 1994. 

A protein with the innocuous name p53 is one of the most frequently cited biological molecules in the Science Citation Index. The "p" in p53 stands for protein and "53" indicates a molecular mass of 53 kDa. The p53 protein plays a fundamental role in human cell growth and mutations in this protein are frequently associated with the formation of tumors. It is estimated that of the 6.5 million people diagnosed with one or another form of cancer each year about half have p53 mutations in their tumor cells and that the vast majority of these mutations are single point mutations. 

By examining some of the over one thousand tumor-causing point mutations of p53 in the light of its structure, we can identify features of p53 that are necessary for tumor suppression. The amino acids most frequently changed in cancer cells are at or near the protein-DNA interface residues that are infrequently mutated, if at all, are in general far from the DNA-binding site. 

Figure 17.14 Model of evolved mutant from cephalosphorinase shuffling. The sequence of the most active cephalosporinase mutant was modeled using the crystal structure of the class C cephalosporinase from Enterobacter cloacae. The mutant and wild-type proteins were 63% identical. This chimeric protein contained portions from three of the starting genes, including Enterobacter (blue), Klebsiella (yellow), and Citrobacter (green), as well as 33 point mutations (red). (Courtesy of A. Crameri.)...

In contrast to macrolides, the targets of (3-lactams, the penicillin binding proteins (PBPs) require several mutations in order to become resistant while simultaneously maintaining their viable function as cell wall transpeptidases/transglycosidases. Thus, in order to achieve clinically relevant resistance Streptococcus pneumoniae uses a unique strategy to rapidly accumulate several point mutations. Due to its natural competence for transformation during respiratory tract... 

Point mutations Protein folding Transcriptional control Frameshiftand nonsense mutations RNA processing Sickle cell disease P-Thalassemia P-Thalassemia P-Thalassemia... 

Figure 49-10. Simplified scheme of the causation of malignant hyperthermia (MIM 145600). At least 17 different point mutations have been detected in the RYRl gene, some of which are associated with central core disease (MIM 117000). It is estimated that at least 50% of families with members who have malignant hyperthermia are linked to the RYRl gene. Some individuals with mutations in the gene encoding DHPR have also been detected it is possible that mutations in other genes for proteins involved in certain aspects of muscle metabolism will also be found.

Mutations (eg, point mutations, or in some cases deletions) in the genes (nuclear or mitochondrial) encoding various proteins, enzymes, or tRNA molecules are the fundamental causes of the inherited cardiomyopathies. Some conditions are mild, whereas others are severe and may be part of a syndrome affecting other tissues. 

Burger M, Burger JA, Hoch RC, Oades Z, Takamori H, Schraufstatter IU. Point mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi s sarcoma herpesvirus-G protein-coupled receptor. 1 Immunol 1999 163(4) 2017-2022. 

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