Conformational Analysis of Genotoxic Benzo[a]pyrene- 7,8-dione-Duplex DNA Adducts Using a Molecular Dynamics Method.

Jin, B,Lee, H M,Kim, S K Adenine Press 2010 Journal of biomolecular structure & dynamics Vol.27 No.4

<P>Benzo[a]pyrene-7,8-quinone (BPQ), a metabolite of the wide spread carcinogen benzo[a]pyrene, has been known to form adducts with DNA bases, namely guanine and adenine. The adducts include stereoisomers of the eight BPQ- G(1,2) and products of the formation of the cyclic five-member ring between BPQ and the G base. The stereochemical characteristics, structural properties, and thermodynamic aspects of the formation of the BPQ-G modified duplexes were investigated in this work using molecular modeling and a molecular dynamics (MD) simulation technique. Three conformations for the BPQ- oligonucleotides adduct showed the most favorable free energy (DeltaG). The molecular plane of the BPQ is nearly perpendicular to the DNA base plane for all three stable adducts. In two adducts, BPQ is located in the minor groove with either anti or syn conformations around the glycosidic bond. One of adducts in which BPQ locates into the major groove with the anti conformation around the glycosidic bond was also energetically possible. The resulting detailed structures of the three conceivable BPQ-oligonucleotide adducts are elucidated in this work.</P>

The effect of thiobarbituric acid on tyrosinase: inhibition kinetics and computational simulation.

Yin, Shang-Jun,Si, Yue-Xiu,Wang, Zhi-Jiang,Wang, Su-Fang,Oh, Sangho,Lee, Sanghyuk,Sim, Seon-Mi,Yang, Jun-Mo,Qian, Guo-Ying,Lee, Jinhyuk,Park, Yong-Doo Adenine Press 2011 Journal of biomolecular structure & dynamics Vol.29 No.3

<P>Tyrosinase plays various roles in organisms and much research has focused on the regulation of tyrosinase activity. We studied the inhibitory effect of thiobarbituric acid (TBA) on tyrosinase. Our kinetic study showed that TBA inhibited tyrosinase in a reversible noncompetitive manner (K(i) 5 14.0 ± 8.5 mM and IC?????? 5 8.0 ± 1.0 mM). Intrinsic and ANS-binding fluorescences studies were also performed to gain more information regarding the binding mechanism. The results showed that no tertiary structural changes were obviously observed. For further insight, we predicted the 3D structure of tyrosinase and simulated the docking between tyrosinase and TBA. The docking simulation was successful with significant scores (binding energy for AutoDock4: -5.52 kcal/mol) and suggested that TBA was located in the active site. The 11 ns molecular dynamics simulation convinced that the four HIS residues (residue numbers: 57, 90, 250, and 282) were commonly responsible for the interaction with TBA. Our results provide a new inhibition strategy that works using an antioxidant rather than targeting the copper ions within the tyrosinase active site.</P>

Towards profiling the gene expression of tyrosinase-induced melanogenesis in HEK293 cells: a functional DNA chip microarray and interactomics studies.

Cho, Ick-Hyun,Lü,, Zhi-Rong,Yu, Jae-Ran,Park, Yong-Doo,Yang, Jun-Mo,Hahn, Myong-Joon,Zou, Fei Adenine Press 2009 Journal of biomolecular structure & dynamics Vol.27 No.3

<P>The overexpression of a single tyrosinase gene can induce conspicuous pigmentation in nonpigmented cells. We hypothesized that some unknown tyrosinase-associated genes are simultaneously regulated by melanin synthesis. To improve understanding of melanogenesis and tyrosinase-associated functions, we attempted to profile the genes that are altered during melanin production in HEK293 cells by using a functional DNA chip microarray. The candidate genes were obtained based on significance analysis of microarray (SAM) and further computational prediction via protein-protein interaction (PPI) mapping suggested that newly detected hub genes were involved in melanogenesis. PPI mapping using bioinformatic tools revealed 8 genes that formed an interaction hub. The yeast two-hybridization results suggested some candidate genes could interact with tyrosinase. The present study provides information to further understand the complex factors associated with tyrosinase-induced melanogenesis and apoptosis. The approach of combining expression data analysis and predicted protein interaction partners can help identify genes involved in pigmentation.</P>

Simulation studies on the stabilities of aggregates formed by fibril-forming segments of alpha-Synuclein.

Yoon, Jeseong,Jang, Soonmin,Lee, Kyunghee,Shin, Seokmin Adenine Press 2009 Journal of biomolecular structure & dynamics Vol.27 No.3

<P>We performed molecular dynamics simulations for various oligomers with different beta-sheet conformations consisting of alpha-Synuclein 71-82 residues using an all atom force field and explicit water model. Tetramers of antiparallel beta-sheet are shown to be stable, whereas parallel sheets are highly unstable due to the repulsive interactions between bulky and polar side chains as well as the weaker backbone hydrogen bonds. We also investigated the stabilities of double antiparallel beta-sheets stacked with asymmetric and symmetric geometries. Our results show that this 12 amino acid residue peptide can form stable beta-sheet conformers at 320K and higher temperatures. The backbone hydrogen bonds in beta-sheet and the steric packing between hydrophobic side chains between beta-sheets are shown to give conformational stabilities.</P>

A comparison of treatment plans using linac-based intensity-modulated radiation therapy and helical tomotherapy for maxillary sinus carcinoma.

Kim, Songyih,Lee, Ik Jae,Kim, Yong Bae,Koom, Woong Sub,Jeon, Byeong Chul,Lee, Chang Geol,Kim, Gwi Eon,Keum, Ki Chang Adenine Press 2009 Technology in cancer research & treatment Vol.8 No.4

<P>This study evaluated whether helical tomotherapy (TOMO) planning could achieve better isodose distribution for the maxillary sinus while concomitantly sparing the adjacent _critical normal organs than linac-based step-and-shoot IMRT (s-IMRT) planning. TOMO and s-IMRT were established for 10 patients with maxillary sinus cancer. The prescription (66 Gy, 30 fractions) was used to cover the planning target volume (PTV) with a 95% isodose line. Each plan was independently optimized using the CORVUS planning system and Tomotherapy Hi-Art system. The treatment plans were compared using dose volume histogram (DVH), a dose homogeneity index (DHI) of the PTV, and equivalent uniform dose (EUD) and DVH of organs at risk (OARs). The TOMO plans demonstrated better dose homogeneity compared to the s-IMRT plans. The average V95% of the TOMO plans was similar to that of the s-IMRT (92.92% vs. 95.07%, respectively), but the average V107% was 0% for TOMO compared with 18.74% for s-IMRT. The average maximum dose reduction was 7 Gy, and DHI increased by 8% for PTV1 in TOMO compared with s-IMRT (79 Gy vs. 71 Gy and, 89% vs. 97%, respectively). The average EUD reduction for the optic nerve was 17%. In summary, planning with TOMO was superior to s-IMRT planning with respect to dose homogeneity within the PTV and sparing of the optic nerve.</P>

Dosimetric comparisons of three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and helical tomotherapy in whole abdominopelvic radiotherapy for gynecologic malignancy.

Kim, Yong Bae,Kim, Joo Ho,Jeong, Kyung Keun,Seong, Jinsil,Suh, Chang Ok,Kim, Gwi Eon Adenine Press 2009 Technology in cancer research & treatment Vol.8 No.5

<P>OBJECTIVES: The goal of this study was to dosimetrically compare 3-dimensional radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and helical tomotherapy (TOMO) plans for whole abdominopelvic radiotherapy (WART) in patients with gynecologic cancer. METHODS: Ten patients were selected for WART planning. Doses were prescribed to planning target volumes (PTVs) as the followings: 30 Gy to PTV-whole abdominopelvis (PTV-WA), 40 Gy to PTV-para-aortic lymph node (PTV-PALN), 44 Gy to PTV-pelvis, and 50 Gy to gross target volume (GTV) in 20 fractions. Dose to whole liver, both kidneys, and spinal cord were constrained below each tissue tolerance, and bone marrow (BM)-sparing technique was adopted in IMRT and TOMO. Dosimetric parameters and treatment times were compared among plans. RESULTS: Calculated doses in TOMO came most closely to the prescribed dose for coverage of PTV-WA, PTV-PALN, PTV-pelvis, and GTV compared to 3DCRT, and IMRT. In normal organs, TOMO had significantly better dosimetric profiles compared to IMRT and 3DCRT. TOMO significantly reduced V(20Gy), and mean dose of whole liver, both kidneys, and spinal cord. The use of BM-sparing technique (BMS) did not impair coverage of target volume in IMRT and TOMO. While IMRT showed no differences of irradiated BM dose using BMS, TOMO with BMS reduced half V(20Gy) of BM compared to TOMO without BMS. CONCLUSIONS: TOMO showed dosimetric superiority in target coverage, sparing BM, and other normal organs compared to 3DCRT and IMRT. Clinical experiences will be needed for evaluation of feasibility of WART using TOMO in patients with gynecologic cancer.</P>

High-throughput integrated analyses for the tyrosinase-induced melanogenesis: microarray, proteomics and interactomics studies.

Lu, Z-R,Seo, E,Yan, L,Yin, S-J,Si, Y-X,Qian, G-Y,Park, Y-D,Yang, J-M Adenine Press 2010 Journal of biomolecular structure & dynamics Vol.28 No.2

<P>The tyrosinase gene was overexpressed in HEK293 cells, and then a DNA microarray and proteomic tools were applied to detect the dysregulated genes in highly pigmented cells. The candidate genes from the microarray were compared to the yeast two-hybridization results. Computational prediction via protein-protein interaction mapping suggested the existence of 66 hub genes in melanogenesis. Most importantly, RNA binding motif protein 9 is newly detected as a putative critical melanogenesis-associated gene in this study. The approach of combining the expression data analysis and predicted protein interaction partners performed in large scales can bring more reliable gene targets for understanding pigmentation.</P>

A proposal for the revision of molecular boundary typology.

Kim, D-S,Won, C-I,Bhak, J Adenine Press 2010 Journal of biomolecular structure & dynamics Vol.28 No.2

<P>Molecular shape is essential in understanding molecular function, and understanding molecular shape requires definition of molecular boundaries. In this paper, we review the conceptual evolution of three molecular boundary types: the van der Waals surface, the Connolly surface, and the Lee-Richards (accessible) surface. Then, we point out the confusion among the names of these surfaces existing in the literature. Since it is desirable to have a well-defined terminology in a discipline, we propose the standard names of the three molecular boundary types and their corresponding volumes in order to maximize consistency among researchers, respect the first individual who defined or computed a surface type, and promote collaboration between biologists and geometers.</P>

High control rate for lymph nodes in cervical cancer treated with high-dose radiotherapy using helical tomotherapy.

Kim, Y J,Kim, J Y,Yoo, S H,Min, B J,Chung, K Z,Seo, S S,Kang, S B,Lim, M C,Hwang, J H,Yoo, H J,Park, S Y Adenine Press 2013 Technology in cancer research & treatment Vol.12 No.1

<P>The purpose of this study was to evaluate whether bulky lymphadenopathy located in the abdominopelvic cavity in cervical cancer can be controlled without severe toxicity by increasing radiation dose using helical tomotherapy. From January 2007 to December 2010, 26 patients with cervical cancer with metastatic lymph nodes (LNs) having at least one short diameter > 1.5?cm were treated with helical tomotherapy. A total of 58 LN sites were treated and the largest LN of each site was evaluated for response. Median follow-up time was 28 months (4-50 months). Median short diameter of the LNs was 1.7?cm (0.7-4.2?cm) with median radiation dose of 62.6?Gy(10) in 2?Gy equivalent dose (53.3-77.9?Gy(10)). Initial LN response was evaluated on imaging obtained within 4 months after radiotherapy. Initial complete response (CR), partial response (PR), and stable disease (SD) were observed in 54, 2 and 2 lesions, respectively. Recurrence occurred in two with CR and progression in one with PR. Therefore, final CR, PR, SD, and progression of disease were observed in 52, 1, 2, and 3, respectively. Actuarial 3-year LN progression-free survival and overall survival (OS) were 63% and 65%, respectively. Multivariate analysis revealed final LN response (CR vs. non-CR) as a strong prognostic factor for OS (p =?0.016). Radiation Therapy Oncology Group grade 2 or more acute and late toxicity was observed in 8 and 1 patients, respectively. The treatment of bulky lymphadenopathy using helical tomotherapy in advanced cervical cancer is highly effective and has acceptable toxicity.</P>

BetaSuperposer: superposition of protein surfaces using beta-shapes.

Kim, Jae-Kwan,Kim, Deok-Soo Adenine Press 2012 Journal of biomolecular structure & dynamics Vol.30 No.6

<P>The comparison between two protein structures is important for understanding a molecular function. In particular, the comparison of protein surfaces to measure their similarity provides another challenge useful for studying molecular evolution, docking, and drug design. This paper presents an algorithm, called the BetaSuperposer, which evaluates the similarity between the surfaces of two structures using the beta-shape which is a geometric structure derived from the Voronoi diagram of molecule. The algorithm performs iterations of mix-and-match between the beta-shapes of two structures for the optimal superposition from which a similarity measure is computed, where each mix-and-match step attempts to solve an NP-hard problem. The devised heuristic algorithm based on the assignment problem formulation quickly produces a good superposition and an assessment of similarity. The BetaSuperposer was fully implemented and benchmarked against popular programs, the Dali and the Click, using the SCOP models. The BetaSuperposer is freely available to the public from the Voronoi Diagram Research Center ( http://voronoi.hanyang.ac.kr ).</P>