Effects of representative point mutations on dynamic behavior of the DISC1-Ndel1 complex: a molecular dynamics study.

It has been found that the development of schizophrenia and some other psychiatric disorders is related to defects in the normal functioning of Disrupted-In-Schizophrenia 1 (DISC1). It is a large-sized protein containing 855 residues and acts as an active hub at the core of many interactions with various proteins. On the other hand, NudE Neurodevelopment Protein 1 Like 1 (Ndel1) plays a role in nervous system development via interaction with the DISC1. It was shown that some point mutations on DISC1 have clinical implications. In line with these reports, here we have used the NMR structure of the wild-type (WT) C-terminal tail of DISC1 in complex with the N-terminal fragment of Ndel1, and have constructed the three-dimensional structures of L62Q and L29Q mutants, as the pathologic variants of the complex. The time-dependent interaction of DISC1 with Ndel1 in the WT complex and mutants was simulated by performing molecular dynamics (MD) simulation using programs in the GROMACS package. It was found that the flexibility of residues in some regions of the protein chains increases, and secondary structural changes from ordered toward unordered one leads to destabilizing of the complex in mutants. Destabilization of the complex upon substitution of Leu by Gln was also confirmed by analysis of the contact map plot.Communicated by Ramaswamy H. Sarma.

Evolutionary adaptation of DHFR via expression of enzyme isoforms with various binding properties and dynamics behavior: a bioinformatics and computational study.

We compared the binding properties and dynamics of three experimentally reviewed isoforms of human dihydrofolate reductase (DHFR). The cytoplasmic variants including isoforms1 and 2 (iso1 and iso2) are produced by alternative splicing; while the mitochondrial form is located in the mitochondria. The iso1 as the canonical sequence contains 187 residues, and iso2 differs from the iso1, where it has 1-52 residues missing at the N-terminus of canonical sequence. Here, the structural models of the iso2 and mitochondrial forms were constructed by the MODELLER program using the crystal structure of the iso1 as the template. Bioinformatics analysis on ligand-bearing structures demonstrates that mitochondrial variant forms more stable complex with ligands compared with iso1 and 2, indicating their different binding properties. The root mean square fluctuation (RMSF) data suggest that C-terminus of iso1 contains two representative highly flexible fragments, while iso2 contains a highly flexible fragment at N-terminus end. Interestingly, both ends of mitochondrial variant have a degree of rigidity. Finally, the observation of differences in structural dynamics and binding properties predicts that the simultaneous existence of enzyme isoforms is a way to increase the speed of the enzyme maneuver in response to various environmental conditions. This prediction needs to be tested experimentally.

Temperature dependent dynamics in highly homologous adenylate kinases.

To correlate the structural features of enzymes to temperature adaptation, we studied psychrophile, mesophile, and thermophile adenylate kinases as model enzymes using bioinformatics and computational tools. Phylogenetic analysis revealed that mesophile and thermophile variants are clustered in one stem of phylogenetic tree and are close to contemporary time, while psychrophile enzyme is more close to their common ancestor. This finding is in good agreement with the process of environmental changes from ice age toward current warm conditions on the earth. We also performed Molecular Dynamics simulation at corresponding temperatures of all enzyme variants including 308, 318, and 328 K. It was found that mesophile enzyme has no distinct deviation of Root Mean Square Deviation (RMSD) and Radius of Gyration (Rg) values from equilibrium states at operating temperature of thermophile enzyme as well as its own optimum temperature. However, psychrophile enzyme undergoes more fluctuations with higher amplitude of change; particularly at 328 K. It was also found that initial increasing of RMSD and Rg for Psychrophile enzyme at all temperatures is occurred gradually; while, the increment of this structural parameters for thermophile enzyme at 328 K is occurred in a highly cooperative and switching manner demonstrating snap structural change of thermophile enzyme in its own temperature. By analysis of Root Mean Square Fluctuation values at different temperatures, we identified two flexible fragments in adenylate kinases so that different dynamic behavior of these regions in mesophile enzyme against operating temperatures of psychrophile and thermophile variants is critical in compensation of flexibility challenges at respective temperatures.

Distribution of dipeptides in different protein structural classes: an effort to find new similarities.

Finding any regularity in the sequences of proteins and determining their correlation with structural features are of great interest for an understanding of molecular biology. We statistically analyzed the relative frequencies of all 400 possible dipeptides in a data set containing randomly selected proteins of different defined structural classes including all-alpha, all-beta, alpha + beta and alpha/beta families. We found that the distribution of dipeptides is not the same for different structural classes, and some of them are significantly far from a random distribution. A tendency of a given amino acid to localize in the first or second position of a dipeptide depending on the structural class of protein was also found. Interestingly, some amino acids may be substituted for each other in the first or second positions of specific dipeptides in each structural class. This finding apparently contrasts with the routine expectation from the viewpoint of amino acid properties, as classically understood.

Neighbor effect and local conformation in protein structures.

In order to determine the preference or avoidance of the first and second positions of individual dipeptides for adopting different structural conformations, we randomly select defined structural groups of proteins from protein data bank and statistically analyzed the distribution of all 400 possible dipeptides in different secondary structural elements. Considering different combinations of α-helix (α), ß strand (ß) and coil (c) including αα, αß, αc, ßß, ßα, ßc, cc, cα, cß conformations, we found that some dipeptides are randomly distributed in these conformations, while others have non-random distribution for a given conformation. Finally, we provide new set of data containing preference and avoidance tendencies that originate from the neighbor effect for each amino acid according to the context of secondary structural element. The output of current work can provide novel data for different fields of structural bioinformatics as well as experiments involving site-directed mutagenesis.

A theoretical study on the characteristics of the intermolecular interactions in the active site of human androsterone sulphotransferase: DFT calculations of NQR and NMR parameters and QTAIM analysis.

A theoretical study at the level of density functional theory (DFT) was performed to characterize noncovalent intermolecular interactions, especially hydrogen bond interactions, in the active site of enzyme human androsterone sulphotransferase (SULT2A1/ADT). Geometry optimization, interaction energy, (2)H, (14)N, and (17)O electric field gradient (EFG) tensors, (1)H, (13)C, (17)O, and (15)N chemical shielding (CS) tensors, Natural Bonding Orbital (NBO) analysis, and quantum theory of atoms in molecules (QTAIM) analysis of this active site were investigated. It was found that androsterone (ADT) is able to form hydrogen bonds with residues Ser80, Ile82, and His99 of the active site. The interaction energy calculations and NBO analysis revealed that the ADT molecule forms the strongest hydrogen bond with Ser80. Results revealed that ADT interacts with the other residues through electrostatic and Van der Waals interactions. Results showed that these hydrogen bonds influence on the calculated (2)H, (14)N, and (17)O quadrupole coupling constants (QCCs), as well as (1)H, (13)C, (17)O, and (15)N CS tensors. The magnitude of the QCC and CS changes at each nucleus depends directly on its amount of contribution to the hydrogen bond interaction.

Static magnetic fields aggravate the effects of ionizing radiation on cell cycle progression in bone marrow stem cells.

In order to evaluate the influence of static magnetic fields (SMF) on the progression of cell cycle as a monitor of presumptive genotoxicity of these fields, the effects of a 15 mT SMF on cell cycle progression in rat bone marrow stem cells (BMSC) were examined. The cells were divided into two groups. One group encountered SMF alone for 5h continuously but the other group exposed with X ray before treatment with SMF. The population of cells did not show any significant difference in the first group but the second group that was exposed with acute radiation before encountering SMF showed a significant increase in the number of cells in G(2)/M phase. So SMF has intensified the effects of X ray, where SMF alone, did not had any detectable influence on cell cycle. These findings suggest that magnetic fields (MF) play their role by increasing the effects of genotoxic agents and because of the greater concentration of free radicals in the presence of radical pair producers, this effect is better detectable.

Effects of halogen substitution on Watson-Crick base pairing: a possible mechanism for radiosensitivity.

The halogen substituent effect on geometries and charge distributions of the A-T base pair derivatives was evaluated using density functional theory at B3LYP/6-31G* level. The results indicate that all of the substitutions affect geometries and charge distributions of the atoms contributing hydrogen bonds. These changes would be the reason of the radiosensitization of these compounds incorporating DNA.