《Acta Crystallographica. Section D, Structural Biology》2018,74(7):606-620

Molecular replacement (MR) has commonly been employed to derive the phase information in protein crystal X‐ray diffraction, but its success rate decreases rapidly when the search model is dissimilar to the target. MR‐REX has been developed to perform an MR search by replica‐exchange Monte Carlo simulations, which enables cooperative rotation and translation searches and simultaneous clash and occupancy optimization. MR‐REX was tested on a set of 1303 protein structures of different accuracies and successfully placed 699 structures at positions that have an r.m.s.d. of below 2 Å to the target position, which is 10% higher than was obtained by Phaser. However, cases studies show that many of the models for which Phaser failed and MR‐REX succeeded can be solved by Phaser by pruning them and using nondefault parameters. The factors effecting success and the parts of the methodology which lead to success are studied. The results demonstrate a new avenue for molecular replacement which outperforms (and has results that are complementary to) the state‐of‐the‐art MR methods, in particular for distantly homologous proteins.  相似文献   

    

María I. Pérez Millán  Sebastian A. Vishnopolska  Alexandre Z. Daly  Juan P. Bustamante  Adriana Seilicovich  Ignacio Bergadá  Débora Braslavsky  Ana C. Keselman  Rosemary M. Lemons  Amanda H. Mortensen  Marcelo A. Marti  Sally A. Camper  Jacob O. Kitzman 《Molecular Genetics & Genomic Medicine》2018,6(4):514-525

  相似文献   

    

Shuaa Basalom  Yannis Trakadis  Roberta Shear  Michel E. Azouz  Isabelle De Bie 《Molecular Genetics & Genomic Medicine》2018,6(3):452-456

  相似文献   

    

《Journal of lipid research》2018,59(10):1880-1892

  相似文献   

    

《Bioorganic chemistry》2018

The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC₅₀ values of 6 and 3.5 µM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC₅₀ > 50 µM). It was demonstrated that compound 4a at 10 µM enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549.  相似文献   

    

Denan Zhang  Lei Liu  Lin Pang  Qing Jin  Kehui Ke  Ming Hu  Jingbo Yang  Weifang Ma  Hongbo Xie  Xiujie Chen 《Journal of cellular biochemistry》2018,119(4):3510-3518

  相似文献   

    

Jianzhong Chen 《Journal of biomolecular structure & dynamics》2018,36(2):351-361

Molecular dynamics (MD) simulations coupled with principal component (PC) analysis were carried out to study functional roles of Mg²⁺ binding to extracellular signal-regulated kinase 2 (ERK2). The results suggest that Mg²⁺ binding heavily decreases eigenvalue of the first principal component and totally inhibits motion strength of ERK2, which favors stabilization of ERK2 structure. Binding free energy predictions indicate that Mg²⁺ binding produces an important effect on binding ability of adenosine triphosphate (ATP) to ERK2 and strengthens the ATP binding. The calculations of residue-based free energy decomposition show that lack of Mg²⁺ weakens interactions between the hydrophobic rings of ATP and five residues I29, V37, A50, L105, and L154. Hydrogen bond analyses also prove that Mg²⁺ binding increases occupancies of hydrogen bonds formed between ATP and residues K52, Q103, D104, and M106. We expect that this study can provide a significant theoretical hint for designs of anticancer drugs targeting ERK2.  相似文献   

    

S. Andrade-Ochoa  J. García-Machorro  Martiniano Bello  L.M. Rodríguez-Valdez  C.A. Flores-Sandoval 《Journal of biomolecular structure & dynamics》2018,36(9):2312-2330

  相似文献   

    

Parthiban Marimuthu  Kalaimathy Singaravelu 《Journal of biomolecular structure & dynamics》2018,36(6):1637-1648

B-cell lymphoma 2 (Bcl-2) family proteins are the central regulators of apoptosis, functioning via mitochondrial outer membrane permeabilization. The family members are involved in several stages of apoptosis regulation. The overexpression of the anti-apoptotic proteins leads to several cancer pathological conditions. This overexpression is modulated or inhibited by heterodimerization of pro-apoptotic BH3 domain or BH3-only peptides to the hydrophobic groove present at the surface of anti-apoptotic proteins. Additionally, the heterodimerization displayed differences in binding affinity profile among the pro-apoptotic peptides binding to anti-apoptotic proteins. In light of discovering the novel peptide/drug molecules that contain the potential to inhibit specific anti-apoptotic protein, it is necessary to understand the molecular basis of recognition between the protein and its binding partner (peptide or ligand) along with its binding energies. Therefore, the present work focused on deciphering the molecular basis of recognition between pro-apoptotic Bak peptide binding to different anti-apoptotic (Bcl-xL, Bfl-1, Bcl-W, Mcl-1, and Bcl-2) proteins using advanced Molecular Dynamics (MD) approach such as Molecular Mechanics-Generalized Born Solvent Accessible. The results from our investigation revealed that the predicted binding free energies showed excellent correlation with the experimental values (r² = .95). The electrostatic (ΔG_ele) contributions are the major component that drives the interaction between Bak peptides and different anti-apoptotic peptides. Additionally, van der Waals (ΔG_vdw) energies also play an indispensible role in determining the binding free energy. Furthermore, the decomposition analysis highlighted the comprehensive information about the energy contributions of hotspot residues involved in stabilizing the interaction between Bak peptide and different anti-apoptotic proteins.  相似文献   

    

《Proteins》2018,86(5):524-535

Extensive research performed on Toll‐like receptor (TLR) signaling has identified residues in the Toll/interleukin‐1 receptor (TIR) domains that are essential for its proper functioning. Among these residues, those in BB loop are particularly significant as single amino acid mutations in this region can cause drastic changes in downstream signaling. However, while the effect of these mutations on the function is well studied (like the P681H mutation in TLR2, the A795P mutation in TLR3, and the P714H mutation in TLR4), their influence on the dynamics and inter‐residue networks is not well understood. The effects of local perturbations induced by these mutations could propagate throughout the TIR domain, influencing interactions with other TIR domain‐containing proteins. The identification of these subtle changes in inter‐residue interactions can provide new insights and structural rationale for how single‐point mutations cause drastic changes in TIR–TIR interactions. We employed molecular dynamics simulations and protein structure network (PSN) analyses to investigate the structural transitions with special emphasis on TLR2 and TLR3. Our results reveal that phosphorylation of the Tyr 759 residue in the TIR domain of TLR3 introduces rigidity to its BB loop. Subtle differences in the intra BB loop hydrogen bonding network between TLR3 and TLR2 are also observed. The PSN analyses indicate that the TIR domain is highly connected and pinpoints key differences in the inter‐residue interactions between the wild‐type and mutant TIR domains, suggesting that TIR domain structure is prone to allosteric effects, consistent with the current view of the influence of allostery on TLR signaling.  相似文献