Identifying the Working Principles of Human Dna Methyltransferase 3a Enzyme by Computational Methods
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Date
2021
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Kadir Has Üniversitesi
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Abstract
DNA metilasyonu, metilasyon deseninin sürdürülmesi ve oluşturulmasından sorumlu epigenetik mekanizmalardan biridir. DNA metiltransferaz 3 (DNMT3) enzim ailesi DNA'nın sıfırdan metilasyonunu düzenler bu nedenle de novo metiltransferazlar olarak adlandırılır. İki üyesi, DNMT3A ve DNMT3B, DNA ve S-Adenosilmetiyonin (SAM) arasındaki reaksiyonu katalize eder. Diğer üyesi olan DNMT3L ise DNA ile doğrudan etkileşime girmese de, DNMT3A ve DNMT3B'ye bağlanarak reaksiyonu allosterik olarak hızlandırır. Ek olarak, reaksiyonun etkinliğinin DNMT3A: DNMT3L kompleksinin oluşumu ile daha da arttığı görülmüştür. DNMT3A: DNMT3L kompleksi, proteinler arasında hidrofobik arayüzün oluştuğu heterodimer ve hem hidrofobik hem de hidrofilik arayüzler içeren heterotetramer formunda olarak bulunur. Bu çalışmada, bu arayüzlerin ve DNMT3L'nin DNMT3A'nın çalışma prensipleri üzerindeki etkisini bulmayı hedefledik. Bu amaç doğrultusunda, DNM3L'nin allosterik etkisini tespit etmek için PCA analizini kullandık. Ek olarak, MD simülasyonu sırasında meydana gelen protein-DNA etkileşimleri hem heterodimer hem de heterotetramer kompleksleri için incelendi.
DNA methylation is one of the epigenetic mechanisms in mammalians, responsible from maintenance and establishment of methylation pattern. DNA methyltransferase 3 (DNMT3) enzyme family modulates methylation from scratch and named as de novo methyltransferases. Two member of this family, DNMT3A and DNMT3B catalyze the reaction in between DNA and S-Adenosylmethionine (SAM). Although other member, DNMT3L, does not interact with DNA directly and catalytically inactive, stimulates of the reaction allosterically by binding to DNMT3A and DNMT3B. Additionally, efficiency of the reaction increases more with formation of DNMT3A:DNMT3L complex. DNMT3A:DNMT3L complex is found as heterodimer, where hydrophobic interface is formed in between proteins, and heterotetramer including both hydrophobic and hydrophilic interfaces. In this study we studied the effect of these interfaces and DNMT3L on working principles of DNMT3A. To that end, PCA analysis is applied to detect allosteric effect of DNM3L. Additionally, protein-DNA interactions that occur during MD simulation are examined for both heterodimer and heterotetramer complexes.
DNA methylation is one of the epigenetic mechanisms in mammalians, responsible from maintenance and establishment of methylation pattern. DNA methyltransferase 3 (DNMT3) enzyme family modulates methylation from scratch and named as de novo methyltransferases. Two member of this family, DNMT3A and DNMT3B catalyze the reaction in between DNA and S-Adenosylmethionine (SAM). Although other member, DNMT3L, does not interact with DNA directly and catalytically inactive, stimulates of the reaction allosterically by binding to DNMT3A and DNMT3B. Additionally, efficiency of the reaction increases more with formation of DNMT3A:DNMT3L complex. DNMT3A:DNMT3L complex is found as heterodimer, where hydrophobic interface is formed in between proteins, and heterotetramer including both hydrophobic and hydrophilic interfaces. In this study we studied the effect of these interfaces and DNMT3L on working principles of DNMT3A. To that end, PCA analysis is applied to detect allosteric effect of DNM3L. Additionally, protein-DNA interactions that occur during MD simulation are examined for both heterodimer and heterotetramer complexes.
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Biyofizik, Biophysics, Biyoistatistik, Biostatistics, Biyomühendislik, Bioengineering, Biyolojik etkileşim, Biological interaction, DNA metilasyon, DNA methylation, Modeller-moleküler, Models-molecular, Yapı dinamiği, Structural dynamics