Molecular dynamic simulation for evaluation of an impact of mutations in a genetic disease

• Project/Area Number: 26330331
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Life / Health / Medical informatics
• Research Institution: Yokohama City University
• Principal Investigator: SHIINA Masaaki 横浜市立大学, 医学部, 助教 (30347299)
• Co-Investigator(Kenkyū-buntansha): 緒方 一博 横浜市立大学, 医学研究科, 教授 (90260330)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 分子動力学 / 構造生物学 / 分子遺伝学 / 分子構造解析 / 遺伝性疾患 / X線結晶構造解析

Outline of Final Research Achievements

Rapid progress in structural biology and molecular genetics is obvious, yet their cooperation remains out of reach. Our aim is to develop in silico pipeline, which enables us to assess the impact of the mutations found by domestic and international genetics laboratories from the structural viewpoint. Specifically, we analyzed the mutations not only by static structural analysis such as homology modeling and free energy change calculation but also by dynamic analysis using molecular dynamics (MD) simulation. We showed that MD is a powerful tool to evaluate effects of gene mutations on protein structure and function.

Research Products

• [Journal Article] A novel GFI1B mutation at the first zinc finger domain causes congenital macrothrombocytopenia (2017)
  • Author(s): Uchiyama Y, Ogawa Y, Kunishima S, Shiina M, Nakashima M, Yanagisawa K, Yokohama A, Imagawa E, Miyatake S, Mizuguchi T, Takata A, Miyake N, Ogata K, Handa H, Matsumoto N
  • Journal Title: British Journal of Haematology Volume: 印刷中 Issue: 6 Pages: 843-847
  • DOI: 10.1111/bjh.14710
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Molecular mechanisms of cooperative binding of transcription factors Runx1-CBFβ-Ets1 on the TCRα gene enhancer (2017)
  • Author(s): Kasahara K, Shiina M, Fukuda I, Ogata K, Nakamura H
  • Journal Title: PloS One Volume: 12 Issue: 2 Pages: e0172654-e0172654
  • DOI: 10.1371/journal.pone.0172654
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing (2017)
  • Author(s): Lardelli RM, Schaffer AE, Eggens VR, ... Matsumoto N, Muramatsu K, Saitsu H, Shiina M, Ogata K, Foulds N, Dobyns WB, Chi NC, Traver D, Spaccini L, Bova SM, Gabriel SB, Gunel M, Valente EM, Nassogne MC, Bennett EJ, Yeo GW, Baas F, Lykke-Andersen J, Gleeson JG
  • Journal Title: Nature Genetics Volume: 49 Issue: 3 Pages: 457-464
  • DOI: 10.1038/ng.3762
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder (2017)
  • Author(s): Mizuguchi T, Nakashima M, Kato M, Yamada K, Okanishi T, Ekhilevitch N, Mandel H, Eran A, Toyono M, Sawaishi Y, Motoi H, Shiina M, Ogata K, Miyatake S, Miyake N, Saitsu H, Matsumoto N
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 5 Pages: 525-529
  • DOI: 10.1038/jhg.2016.163
  • NAID: 40021210259
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Biallelic mutations in MYPN, encoding Myopalladin, are associated with childhood-onset, slowly progressive nemaline myopathy (2017)
  • Author(s): Miyatake S, Mitsuhashi S, Hayashi YK, Purevjav E, Nishikawa A, Koshimizu E, Suzuki M, Yatabe K, Tanaka Y, Ogata K, Kuru S, Shiina M, Tsurusaki Y, Nakashima M, Mizuguchi T, Miyake N, Saitsu H, Ogata K, Kawai M, Towbin J, Nonaka I, Nishino I, Matsumoto N
  • Journal Title: American Journal of Human Genetics Volume: 100 Issue: 1 Pages: 169-178
  • DOI: 10.1016/j.ajhg.2016.11.017
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Distal arthrogryposis with variable clinical expression caused by TNNI2 mutation (2017)
  • Author(s): Culic V, Miyake N, Jankovic S, Petrovic D, Simunovic M, Dapic T, Shiina M, Ogata K, Matsumoto N
  • Journal Title: Human Genome Variation Volume: 3 Issue: 1 Pages: 16035-16035
  • DOI: 10.1038/hgv.2016.35
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The first report of Japanese patients with asparagine synthetase deficiency (2017)
  • Author(s): Yamamoto T, Endo W, Ohnishi H, Kubota K, Kawamoto N, Inui T, Imamura A, Takanashi JI, Shiina M, Saitsu H, Ogata K, Matsumoto N, Haginoya K, Fukao T
  • Journal Title: Brain Development Volume: 39 Issue: 3 Pages: 236-242
  • DOI: 10.1016/j.braindev.2016.09.010
  • Peer Reviewed
• [Journal Article] Biallelic TBCD mutations cause early-onset neurodegenerative encephalopathy (2017)
  • Author(s): Miyake N, Fukai R, Ohba C, ... Shiina M, Ogata K, Okuno-Yuguchi J, Fueki N, Ogiso Y, Suzumura H, Watabe Y, Imataka G, Leong HY, Fattal-Valevski A, Kramer U, Miyatake S, Kato M, Okamoto N, Sato Y, Mitsuhashi S, Nishino I, Kaneko N, Nishiyama A, Tamura T, Mizuguchi T, Nakashima M, Tanaka F, Saitsu H, Matsumoto N
  • Journal Title: American Journal of Human Genetics Volume: 99 Issue: 4 Pages: 950-961
  • DOI: 10.1016/j.ajhg.2016.08.005
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phenotypic spectrum of GNAO1 variants: Epileptic encephalopathy to involuntary movements with severe developmental delay (2016)
  • Author(s): Saitsu H, Fukai R, Ben-Zeev B, Sakai Y, Mimaki M, Okamoto N, Suzuki Y, Monden Y, Saito H, Tziperman B, Torio M, Akamine S, Takahashi N, Osaka H, Yamagata T, Nakamura K, Tsurusaki Y, Nakashima M, Miyake N, Shiina M, Ogata K, Matsumoto N
  • Journal Title: Eur J Hum Genet Volume: 24 Issue: 1 Pages: 129
  • DOI: 10.1038/ejhg.2015.92
  • URL: https://pure.teikyo.jp/en/publications/06a45aed-f2e5-424a-b8d1-3e9a6923fdc5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biallelic mutations in nuclear pore complex subunit NUP107 cause early-childhood-onset steroid-resistant nephrotic syndrome (2015)
  • Author(s): Miyake N, Tsukaguchi H, Koshimizu E, Shono A, Matsunaga S, Shiina M, Mimura Y, Imamura S, Hirose T, Okudela K, Nozu K, Akioka Y, Hattori M, Yoshikawa N, Kitamura A, Cheong HI, Kagami S, Yamashita M, Fujita A, Miyatake S, Tsurusaki Y, Nakashima M, Saitsu H, Ohashi K, Imamoto N, Ryo A, Ogata K, Iijima K, Matsumoto N
  • Journal Title: Am J Hum Genet Volume: 97(4) Issue: 4 Pages: 555-566
  • DOI: 10.1016/j.ajhg.2015.08.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of HOXD4 Mutations in Spinal Extradural Arachnoid Cyst (2015)
  • Author(s): Ogura Y, Miyake N, Kou I, Iida A, Nakajima M, Takeda K, Fujibayashi S, Shiina M, Okada E, Toyama Y, Iwanami A, Ishii K, Ogata K, Asahara H, Matsumoto N, Nakamura M, Matsumoto M, Ikegawa S
  • Journal Title: PLoS One Volume: 10(11) Issue: 11 Pages: e0142126-e0142126
  • DOI: 10.1371/journal.pone.0142126
  • NAID: 120005763410
  • Peer Reviewed / Open Access
• [Journal Article] Short-lasting unilateral neuralgiform headache attacks with ispilateral facial flushing is a new variant of paroxysmal extreme pain disorder (2015)
  • Author(s): Imai N, Miyake N, Saito Y, Kobayashi E, Ikawa M, Manaka S, Shiina M, Ogata K, Matsumoto N
  • Journal Title: J Headache Pain Volume: 16(1) Issue: 1 Pages: 519-519
  • DOI: 10.1186/s10194-015-0519-3
  • Peer Reviewed / Open Access
• [Journal Article] A novel allosteric mechanism on protein-DNA interactions underlying the phosphorylation-dependent regulation of Ets1 target gene expressions (2015)
  • Author(s): Shiina M, Hamada K, Inoue-Bungo T, Shimamura M, Uchiyama A, Baba S, Sato K, Yamamoto M, Ogata K
  • Journal Title: J Mol Biol Volume: 427(8) Issue: 8 Pages: 1655-1669
  • DOI: 10.1016/j.jmb.2014.07.020
  • Peer Reviewed / Open Access
• [Journal Article] Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb (2015)
  • Author(s): Nakashima M, Saitsu H, Takei N, Tohyama J, Kato M, Kitaura H, Shiina M, Shirozu H, Masuda H, Watanabe K, Ohba C, Tsurusaki Y, Miyake N, Zheng Y, Sato T, Takebayashi H, Ogata K, Kameyama S, Kakita A, Matsumoto N
  • Journal Title: Ann. Neurol. Volume: 78 Issue: 3 Pages: 375-386
  • DOI: 10.1002/ana.24444
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders (2015)
  • Author(s): Ohba C, Shiina M, Tohyama J, Haginoya K, Lerman-Sagie T, Okamoto N, Blumkin L, Lev D, Mukaida S, Nozaki F, Uematsu M, Onuma A, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Kato M, Ogata K, Saitsu H, Matsumoto N
  • Journal Title: Epilepsia Volume: 印刷中 Issue: 6 Pages: 841-848
  • DOI: 10.1111/epi.12987
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel compound heterozygous LIAS mutations cause glycine encephalopathy (2015)
  • Author(s): Tsurusaki Y, Tanaka R, Shimada S, Shimojima K, Shiina M, Nakashima M, Saitsu H, Miyake N, Ogata K, Yamamoto T, Matsumoto N
  • Journal Title: J Hum Genet Volume: 60(10) Issue: 10 Pages: 631-635
  • DOI: 10.1038/jhg.2015.72
  • Peer Reviewed / Open Access
• [Journal Article] De novo DNM1 mutations in two cases of epileptic encephalopathy. (2015)
  • Author(s): Nakashima M, Kouga T, Lourenço CM, Shiina M, Goto T, Tsurusaki Y, Miyatake S, Miyake N, Saitsu H, Ogata K, Osaka H, Matsumoto N.
  • Journal Title: Epilepsia Volume: Epub 2015 Nov 27. Issue: 1
  • DOI: 10.1111/epi.13257
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] De novo SOX11 mutations cause Coffin-Siris syndrome (2014)
  • Author(s): Tsurusaki Y, Ohashi H, Phadke S, Koshimizu E, Kou I, Shiina M, Suzuki T, Okamoto N, Imamura S, Yamashita M, Watanabe S, Yoshiura K-i, Kodera H, Miyatake S, Nakashima N, Saitsu H, Ogata K, Ikegawa S, Miyake N, and Matsumoto N.
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 4011-4011
  • DOI: 10.1038/ncomms5011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expanding the phenotypic spectrum of TUBB4A-associated (2014)
  • Author(s): Miyatake S, Osaka H, Shiina M, Sasaki M, Takanashi J, Haginoya K, Wada T,
  • Journal Title: Neurology Volume: 82(24) Issue: 24 Pages: 2230-7
  • DOI: 10.1212/wnl.0000000000000535
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A hemizygous GYG2 mutation and Leigh syndrome: a possible link? (2014)
  • Author(s): Imagawa E, Osaka H, Yamashita A, Shiina M, Takahashi E, Sugie H, Nakashima M, Tsurusaki Y, Saitsu H, Ogata K, Matsumoto N, Miyake N.
  • Journal Title: Hum Genet. Volume: 133(2 Issue: 2 Pages: 225-34
  • DOI: 10.1007/s00439-013-1372-6
  • Peer Reviewed / Open Access
• [Journal Article] Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation (2014)
  • Author(s): Doi H, Ushiyama M, Baba T, Tani K, Shiina M, Ogata K, Miyatake S, Yuzawa YF, Tsuji S, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Ikeda S, Tanaka F, Matsumoto N, Yoshida K
  • Journal Title: Sci Rep Volume: 4 Issue: 1 Pages: 7132-7132
  • DOI: 10.1038/srep07132
  • NAID: 120007100602
  • Peer Reviewed / Open Access
• [Journal Article] Crystallization of the Ets1-Runx1-CBFβ-DNA complex formed on the TCRα gene enhancer (2014)
  • Author(s): Shiina M, Hamada K, Inoue-Bungo T, Shimamura M, Baba S, Sato K, Ogata K
  • Journal Title: Acta Crystallogr F Struct Biol Commun Volume: 70 Issue: 10 Pages: 1380-1384
  • DOI: 10.1107/s2053230x14018470
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Search for anti-leukemic drugs targeting the transcription factor Runx1 by INTENDD (2017)
  • Author(s): Shiina M, Baba S, Uchiyama A, Okada C, Tanaka T, Ikeda K, Kawakita S, Matsuzaki T, Komatsu H, Hosoda M, Ogata K
  • Organizer: The 137th Annual Meeting of the Pharmaceutical Society of Japan, 3rd International Symposium for Medicinal Sciences
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-03-24
  • Int'l Joint Research / Invited
• [Presentation] パートナー因子によるEts1のコンフォーメーション分布の変化と活性制御機構の解析 (2016)
  • Author(s): 内山晃子，椎名政昭，浜田恵輔，馬場しほ，岡田千佳子，鈴木香絵，佐藤 光，緒方一博
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] 転写因子Ets1の天然変性領域のリン酸化によるDNA結合制御機構の速度論的解析 (2016)
  • Author(s): 椎名政昭，笠原浩太，肥後順一，馬場しほ，内山晃子，岡田千佳子，浜田恵輔，佐藤 光，中村春木，緒方一博
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-03
• [Presentation] Molecular behavior of a higher-order complex of multiple transcription factors on enhancer site upon phosphorylation (2016)
  • Author(s): Ogata K, Shiina M, Kasahara K, Higo J, Hamada K, Nakamura H
  • Organizer: 6th International Conference on Structural Biology (Structural Biology 2016)
  • Place of Presentation: New Orleans (Hilton New Orleans Airport Hotel), USA
  • Year and Date: 2016-08-22
  • Int'l Joint Research / Invited
• [Presentation] Molecular mechanism for modulation of a multiple transcription factor complex formed on enhancer site up on phosphorylation (2016)
  • Author(s): Ogata K, Shiina M, Kasahara K, Higo J, Hamada K, Nakamura H
  • Organizer: 5th International Conference and Exhibition on Metabolomics
  • Place of Presentation: Hyatt Regency Osaka（大阪府大阪市）
  • Year and Date: 2016-05-16
  • Int'l Joint Research / Invited
• [Presentation] Ets1とRunx1のエンハンサー上での立体的な位置関係と協調性 (2015)
  • Author(s): 内山晃子，椎名政昭，浜田恵輔，豊後泰子，嶋村麻利子，緒方一博
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市中央区）
  • Year and Date: 2015-12-01
• [Presentation] Kinetic characterization of a DNA binding activity of the transcription factor Ets1 and its regulation by phosphorylation in an intrinsically disordered region (2015)
  • Author(s): Shiina M, Kasahara K, Higo J, Baba S, Hamada K, Uchiyama A, Suzuki K, Sato K, Nakamura H, Ogata K
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市中央区）
  • Year and Date: 2015-12-01
• [Presentation] 分子構造に基づく転写因子Nuclear factor (erythroid-derived2)-like2(Nrf2)の抗酸化剤応答配列認識機構の解析 (2015)
  • Author(s): 鈴木香絵，椎名政昭，浜田恵輔，石川涼平，金井達哉，豊後泰子，岡田千佳子，馬場しほ，鈴木隆史，太田 力，山本雅之，緒方一博
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市中央区）
  • Year and Date: 2015-12-01
• [Presentation] Kinetic characterization of a DNA binding activity of the transcription factor Ets1 and its regulation by phosphorylation at an intrinsically disordered region (2014)
  • Author(s): Shiina M, Hamada K, Bungo-Inoue T, Shimamura M, Uchiyama A, Baba S, Sato K, Suzuki K, Yamamoto M, Ogata K
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 (神奈川県・横浜市)
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Orientation of Ets1 and Runx1 binding sites on enhancers and their cooperative regulation (2014)
  • Author(s): Uchiyama A, Shiina M, Hamada K, Bungo T, Shimamura M, Ogata K
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 (神奈川県・横浜市)
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Regulation of DNA binding of Ets1 by phosphorylation in an intrinsic disordered region (2014)
  • Author(s): 椎名政昭，浜田恵輔，井上－豊後泰子，嶋村麻利子，馬場しほ，内山晃子，鈴木香絵，タヒロフ タヒール，緒方一博
  • Organizer: 第14回日本蛋白質科学会年会
  • Place of Presentation: ワークピア横浜 (神奈川県・横浜市）
  • Year and Date: 2014-06-25 – 2014-06-27
  • Invited
• [Book] 見てわかる構造生命科学 生命科学研究へのタンパク質構造の利用 中村春木編 (2014)
  • Author(s): 椎名政昭，緒方一博
  • Total Pages: 28
  • Publisher: 化学同人
• [Remarks] 横浜市立大学大学院医学研究科生化学教室ホームページ
  • URL: http://www-user.yokohama-cu.ac.jp/~seika/index.html
• [Remarks] 横浜市立大学大学院医学研究科生化学
  • URL: http://www-user.yokohama-cu.ac.jp/~seika/index.html