Hydrogen bonds and asymmetrical heat diffusion in a-Helices. A Computational Analysis

In this work, we report the heat rectifying capability of a-helices. Using molecular dynamics simulations we show an increased thermal diffusivity in the C-Terminal to N-Terminal direction of propagation. The origin of this effect seems to be a function of the particular orientation of the hydrogen bonds stabilizing these a-helices. Our results may be relevant for the design of thermal rectification devices for materials science and lend support to the role of normal length hydrogen bonds in the asymmetrical energy flow in proteins

Lack of Response to Imatinib in Melanoma Carrying Rare KIT Mutation р.T632I

Approximately 15% of acral and mucous melanomas carry activating mutations in KIT oncogene. There is a diversity of spectrum of KIT mutations, with some of them rendering tumors responsive to imatinib, while others being imatinib-resistant or not studied yet. Here we present an acral melanoma patient with KIT р.T632I mutation, who failed to respond to imatinib

How missense mutations in receptors tyrosine kinases impact constitutive activity and alternate drug sensitivity: insights from molecular dynamics simulations

The fundamental oncology-related research is required for a deeper understanding of the molecular mechanisms associated with the normal and/or abnormal protein functions, which are closely related with structure and dynamics of the macromolecules involved in these process. The most common origin of oncogenic events is related to missense mutations. Mutation-induced structural effects promoted by oncogenic mutations in receptor tyrosine kinases (RTKs), are not yet fully characterized. Computational biology completes and enriches experimental data, producing a novel vision of molecular mechanisms governing RTKs activity. In series of our papers, we studied the structural and dynamical features of native and mutated RTKs from III family (KIT and CSF-1R), yielding a detailed description of their mechanisms of activation, ligand-depend for the native proteins and constitutive for the distinct mutants. The mechanisms of RTKs activation are described in terms of allosteric regulation between coupled regulating fragments of the protein, juxta-membrane region (JMR) and activation (A-) loop. As some mutations promote resistance to the clinically-used drugs, we analyzed the affinity of imatinib to these therapeutic targets. The computationally-obtained (in silico) data were correlated with in vivo and in vitro observations, thus validating our numerically-based accounts. Going forward, clinical validation of cancer-related models and simulations are cornerstones key of translation of in silico data into biomedical research, at clinical and pharmacological levels

Allosteric Communication Pathways and Thermal Rectification in PDZ-2 Protein: A Computational Study

Allosteric communication in proteins is a central and yet unsolved problem of structural biochemistry. Previous findings, from computational biology (Ota and Agard, 2005), have proposed that heat diffuses in a protein through cognate protein allosteric pathways. This work studied heat diffusion in the well-known PDZ-2 protein, and confirmed that this protein has two cognate allosteric pathways and that heat flows preferentially through these. Also, a new property was also observed for protein structures - heat diffuses asymmetrically through the structures. The underling structure of this asymmetrical heat flow was a normal length hydrogen bond (~2.85 {\AA}) that acted as a thermal rectifier. In contrast, thermal rectification was compromised in short hydrogen bonds (~2.60 {\AA}), giving rise to symmetrical thermal diffusion. Asymmetrical heat diffusion was due, on a higher scale, to the local, structural organization of residues that, in turn, was also mediated by hydrogen bonds. This asymmetrical/symmetrical energy flow may be relevant for allosteric signal communication directionality in proteins and for the control of heat flow in materials science.Comment: 29 pages, 8 Figures. All Results Unchanged. Changed Title. Improved Grammar. Added references. Corrected typos. Elimination of the "Knocking" argument for Asp5-Lys91 Interaction in Results and in Discussion section

Trading in cooperativity for specificity to maintain uracil-free DNA

Members of the dUTPase superfamily play an important role in the maintenance of the pyrimidine nucleotide balance and of genome integrity. dCTP deaminases and the bifunctional dCTP deaminase-dUTPases are cooperatively regulated by dTTP. However, the manifestation of allosteric behavior within the same trimeric protein architecture of dUTPases, the third member of the superfamily, has been a question of debate for decades. Therefore, we designed hybrid dUTPase trimers to access conformational states potentially mimicking the ones observed in the cooperative relatives. We studied how the interruption of different steps of the enzyme cycle affects the active site cross talk. We found that subunits work independently in dUTPase. The experimental results combined with a comparative structural analysis of dUTPase superfamily enzymes revealed that subtile structural differences within the allosteric loop and the central channel in these enzymes give rise to their dramatically different cooperative behavior. We demonstrate that the lack of allosteric regulation in dUTPase is related to the functional adaptation to more efficient dUTP hydrolysis which is advantageous in uracil-DNA prevention

Trading in cooperativity for specificity to maintain uracil-free DNA

Members of the dUTPase superfamily play an important role in the maintenance of the pyrimidine nucleotide balance and of genome integrity. dCTP deaminases and the bifunctional dCTP deaminase-dUTPases are cooperatively regulated by dTTP. However, the manifestation of allosteric behavior within the same trimeric protein architecture of dUTPases, the third member of the superfamily, has been a question of debate for decades. Therefore, we designed hybrid dUTPase trimers to access conformational states potentially mimicking the ones observed in the cooperative relatives. We studied how the interruption of different steps of the enzyme cycle affects the active site cross talk. We found that subunits work independently in dUTPase. The experimental results combined with a comparative structural analysis of dUTPase superfamily enzymes revealed that subtile structural differences within the allosteric loop and the central channel in these enzymes give rise to their dramatically different cooperative behavior. We demonstrate that the lack of allosteric regulation in dUTPase is related to the functional adaptation to more efficient dUTP hydrolysis which is advantageous in uracil-DNA prevention

Allosteric Communication across the Native and Mutated KIT Receptor Tyrosine Kinase

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