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      Mutation L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling

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          Abstract

          Anaplastic lymphoma kinase (ALK) has been regarded as a promising drug target in the treatment of tumors and the mutation L1196M induces different levels of drug resistance toward the existing inhibitors.

          Abstract

          Anaplastic lymphoma kinase (ALK) has been regarded as a promising drug target in the treatment of tumors and the mutation L1196M induces different levels of drug resistance toward the existing inhibitors. Free energy perturbation (FEP) coupled with umbrella sampling simulation is used to investigate the conformational change of ALK induced by L1196M and drug-resistant mechanisms of L1196M on four inhibitors VGH, 3U9, 5P8 and IV7. Dynamics analysis shows that L119M produces significant influences on the flexibility of the loops L1 and L2 in ALK. FEP calculations suggest that the drug-resistant intensity of L1196M toward inhibitors decreases in the order 3U9 > VGH > 5P8 > IV7, in accordance with the experimentally determined results. Moreover, statistical analysis of hydrophobic contacts of inhibitors with separate residues in ALK further demonstrates that the decrease in the hydrophobic interactions of inhibitors with L1256 mostly drives drug resistance of L1196M toward inhibitors. The calculations of potential of mean force (PMF) based on umbrella sampling simulations indicate that the free energies of inhibitor-L1196M ALKs are lower than those of inhibitor-wild ALKs. This study is expected to provide significant theoretical support which would help in the design of potent inhibitors alleviating the drug resistance of L1196M in ALK.

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          Canonical sampling through velocity-rescaling

          We present a new molecular dynamics algorithm for sampling the canonical distribution. In this approach the velocities of all the particles are rescaled by a properly chosen random factor. The algorithm is formally justified and it is shown that, in spite of its stochastic nature, a quantity can still be defined that remains constant during the evolution. In numerical applications this quantity can be used to measure the accuracy of the sampling. We illustrate the properties of this new method on Lennard-Jones and TIP4P water models in the solid and liquid phases. Its performance is excellent and largely independent on the thermostat parameter also with regard to the dynamic properties.
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            Very fast empirical prediction and rationalization of protein pKa values.

            A very fast empirical method is presented for structure-based protein pKa prediction and rationalization. The desolvation effects and intra-protein interactions, which cause variations in pKa values of protein ionizable groups, are empirically related to the positions and chemical nature of the groups proximate to the pKa sites. A computer program is written to automatically predict pKa values based on these empirical relationships within a couple of seconds. Unusual pKa values at buried active sites, which are among the most interesting protein pKa values, are predicted very well with the empirical method. A test on 233 carboxyl, 12 cysteine, 45 histidine, and 24 lysine pKa values in various proteins shows a root-mean-square deviation (RMSD) of 0.89 from experimental values. Removal of the 29 pKa values that are upper or lower limits results in an RMSD = 0.79 for the remaining 285 pKa values. Proteins 2005. 2005 Wiley-Liss, Inc.
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              The anaplastic lymphoma kinase in the pathogenesis of cancer.

              Tyrosine kinases are involved in the pathogenesis of most cancers. However, few tyrosine kinases have been shown to have a well-defined pathogenetic role in lymphomas. The anaplastic lymphoma kinase (ALK) is the oncogene of most anaplastic large cell lymphomas (ALCL), driving transformation through many molecular mechanisms. In this Review, we will analyse how translocations or deregulated expression of ALK contribute to oncogenesis and how recent genetic or pharmacological tools, aimed at neutralizing its activity, can represent the basis for the design of powerful combination therapies.
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                Author and article information

                Journal
                PPCPFQ
                Physical Chemistry Chemical Physics
                Phys. Chem. Chem. Phys.
                Royal Society of Chemistry (RSC)
                1463-9076
                1463-9084
                2017
                2017
                : 19
                : 44
                : 30239-30248
                Affiliations
                [1 ]School of Science, Shandong Jiaotong University
                [2 ]Jinan
                [3 ]China
                [4 ]Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
                [5 ]Shanghai
                Article
                10.1039/C7CP05418A
                29109998
                ff06f0b4-17bc-4ada-bb24-b7535a237fc2
                © 2017

                http://rsc.li/journals-terms-of-use

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