شماره کتابشناسی ملی
شماره
۱۵۸۱۹پ
زبان اثر
زبان متن نوشتاري يا گفتاري و مانند آن
per
عنوان و نام پديدآور
عنوان اصلي
مطالعه ی ساختاری و تأثیر جهش های ژنی پروتئین ۵۳ pدخیل در سرطان تخمدان با استفاده از محاسبات مولکولی
نام نخستين پديدآور
/صدیقه سعادت علی قیالو
وضعیت نشر و پخش و غیره
نام ناشر، پخش کننده و غيره
: مرکز تحقیقات علوم پایه
تاریخ نشرو بخش و غیره
، ۱۳۹۴
یادداشتهای مربوط به نشر، بخش و غیره
متن يادداشت
چاپی
یادداشتهای مربوط به پایان نامه ها
جزئيات پايان نامه و نوع درجه آن
کارشناسی ارشد
نظم درجات
فیتوشیمی
زمان اعطا مدرک
۱۳۹۴/۱۱/۲۰
کسي که مدرک را اعطا کرده
تبریز
یادداشتهای مربوط به خلاصه یا چکیده
متن يادداشت
سرطان تخمدان دومین نئوپلاسم شایع زنان است .این سرطان مانند دیگر سرطان ها از رشد بی رویه ی سلولهای عادی که غالبا به علت عملکرد نادرست پروتئین p۵۳ است، شروع می شود .پروتئین p۵۳ یک فاکتور رونویسی است که می تواند بیان صدها ژن را در پاسخ به عوامل مختلف محیطی و ذاتی تغییر دهد .این پروتئین با بیش از ۱۰۰ پروتئین سلولی دیگر برهمکنش دارد و مسیر های مختلف سلولی را تنظیم می کند .ژن TP۵۳ جهش یافته ترین ژن در ژنوم پستانداران است و در بیش از ۵۰ از سرطان ها به صورت جهش یافته حضور دارد .مطالعات مختلف نشان می دهد جهش ژنی TP۵۳ در سرطان تخمدان بسیار بالاست طوری که فراوانی آن از ۱۵ در مراحل اولیه تا ۸۱ در مراحل پیشرفته متغیر است .بیشترین فراوانی جهش های بدمعنی در این نوع سرطان در نقاط حساس کدون مربوط به R۲۷۳H, R۱۷۵H, R۲۴۸W, H۱۷۹R, R۲۴۸Q, R۲۷۳C, G۲۴۵S صورت می گیرد .در این پایان نامه ابعاد بیوفیزیکی جهش های پروتئین p۵۳ با استفاده از مطالعات دینامیک مولکولی به کمک نرم افزار گرومکس مورد مطالعه قرار گرفت .بدین منظور دمین اتصال به DNA پروتئین p۵۳ به صورت دایمری از زنجیره های A و B استفاده شد .با توجه به فراوانی کلی جهش های پروتئین p۵۳ دخیل در سرطان و به طور خاص در انواع سرطان تخمدان، چهار نوع مختلف از جهش های جایگزینی شاملR۲۷۳H ،R۲۴۸Q ،R۱۷۵H ، G۲۴۵S به صورت جداگانه و در ترکیب با یکدیگر مورد مطالعه قرار گرفت . این جهش ها در دو دسته ی تماسی(R۲۷۳H ،R۲۴۸Q ، (که در تماس با DNA هستند و جهش های کنفورماسیونی(R۱۷۵H ، G۲۴۵S) که در کنفورماسیون کلی سیستم اثر دارند، قرار می گیرد ..نتایج حاصل از این پژوهش نشان می دهد که تغییرات حاصله تحت تاثیر جهش های مذکور اثرات یکنواختی بر ساختار پروتئین در دو زنجیره ندارد و زنجیره ی A و B رفتار متفاوتی در تمامی آنالیزهای انجام شده برای هر دو گروه از جهش ها و در ترکیب انها با یکدیگر نشان می دهند .بر طبق نتایج حاصله این تغییرات در زنجیره ی A شدیدتر و نوسانات بیشتری دارد که علت آن را می توان به نزدیک تر بودن زنجیره B نسبت به A برای مولکول DNA نسبت داد .اینترکشن های بین پروتئین و DNA در زنجیره ی B مانع از تغییرات زیاد در این زنجیره می شود .داده های محاسباتی بیانگر این است که تمامی جهش های ساختاری و تماسی در پروتئین p۵۳ باعث ناپایداری انرژی در کانفورماسیون پروتئین شده اند .مطالعه همزمان تاثیر جهش ها نشان دهنده تغییرات ملموس تر در" ساختار پروتئین "و" انرژی پایداری "آن در مقایسه با تاثیرات جداکانه جهش هاست .از داده های بدست آمده می توان استنباط کرد دمین حفاظت شده این پروتئین شدیدا به کوچکترین تغییرات در ساختار دوم، انرژی پایداری و انعطاف پذیری رزیدوها حساس است طوری که هر تغییر کوچک تحت تاثیر جهش نقطه ای باعث تغییراتی در برهم کنش این پروتئین با دیگر پروتئین ها و DNA می شود و در نتیجه سرنوشت سلولی تغییر کرده و سلول در خطر سرطانی شدن قرار میگیرد
متن يادداشت
Ovarian cancer is the second common gynecological neoplasm. This cancer like the other ones begins when cells start to grow out of control, that is mostly because of the inactivation of p53 functions. Tumor protein p53 is a transcription factor that controls response to several different cellular stresses. TP53 is the most commonly mutated gene in tumors with up to 50 mutation in different types of cancers. The most common oncogenic p53 mutations among ovarian cancer are missense hotspot mutations at codons R273H, R175H, R248W, R179H, R248Q, R273C. In this thesis, we have studied the biophysical aspects of p53 protein mutations using molecular dynamics (MD) simulation by the help of GROMACS (version 5.0.4) package. We have focused on the DNA binding dimer domains of p53 structure. A number of eight simulations were performed using wild-type p53 and different mutants as R273H, R248W (DNA contact mutations) and R175H, G245S (conformational mutations) separately and in combination states. The results of this study showed that the point mutations caused different structural effects on the A and B chains of protein although they are homodimmer. Since, the protein's B chain is closer to DNA and easily interacts with DNA that culminated in higher structural stability of B chain against point mutations effects. Data indicated that the mutations have synergetic effects on the protein's conformation, since using four different mutations of R273H, R248W , R175H, G245S in concomitant, resulted in higher proteins structural changes. From the data, we can conclude that the conserved domain of this protein is highly sensitive to anychanges in secondary structure, protein stability and residues' flexibility. Consequently, any possible structural changes by point mutations cause to appearance of malfunction in the action of p53 such as the interaction with other proteins and DNA, resulting in a change in cell fate and cancer risk. Ovarian cancer is the second common gynecological gyneocological neoplasm. This cancer like the other ones begins when cells start to grow out of control, that is mostly because of the inactivation of p53 functions. Tumor protein p53 P53 is a transcription factor that controls response to several different cellular stresses. TP53 is the most commonly mutated gene in tumors with up to 50 mutation in different types of cancers. The most common oncogenic p53 mutations among ovarian cancer are missense hotspot mutations at codons R273H, R175H, R248W, R179H, R248Q, R273C. In this thesis, we have tried to study studied the biophysical aspects of p53 protein mutations using molecular dynamics (MD) studies. All simulation by the help of were performed with the GROMACS (version 5.0.4) package. and Each mutant system was prepared with the SPDVview (version 4-10). In this study, we We have focused on the DNA binding dimer domains of p53 structure. A number of eight simulations were performed using dimer structure of DNA binding domain. we perform a MD simulation of the p53 dimer wild- type p53 and different mutants as R273H, R248W (DNA contact mutations) and R175H, G245S (conformational mutations) versions of the p53 protein, individually separately and in combination with each otherstates. The results of this study showed that the point Changes resulting from this mutations caused different structural effects on the A and B chains of protein although they are homodimmer. doesnt have a uniform impact on the structure of protein in the both chains. Since, the protein's B chain is closer to DNA and easily interacts with DNA that culminated in higher structural stability of B chain against point mutations effects. Data indicated that the mutations have synergetic effects on the protein's conformation, since using four different mutations of R273H, R248W , R175H, G245S in concomitant, resulted in higher proteins structural changes. According to the results, these changes in chain A stronger and more volatility. Which could be due to this fact that the B chain is closer to DNA than A chain and the Interactions between proteins and DNA in the B chain prevent large changes in this chain. Computed data indicate that all mutations in the p53 protein cause energy instability in protein conformation. The study of mutations in combination with each other shows more tangible changes in protein structure and the Sustainable Energy Compared with the impact of the individual mutation. From the data obtained, we can conclude that the conserved domain of this protein is highly sensitive to anythe smallest changes in secondary structure, protein stability and, residues' flexibility. So that Consequently, any possible structural small changes by point mutations cause to appearance of malfunction in the action of p53 such aschanges in the interaction of this protein with other proteins and DNA, Resulting resulting in a change in cell fate and cancer risk. Ovarian cancer is the second common gynecological gyneocological neoplasm. This cancer like the other ones begins when cells start to grow out of control, that is mostly because of the inactivation of p53 functions. Tumor protein p53 P53 is a transcription factor that controls response to several different cellular stresses. TP53 is the most commonly mutated gene in tumors with up to 50 mutation in different types of cancers. The most common oncogenic p53 mutations among ovarian cancer are missense hotspot mutations at codons R273H, R175H, R248W, R179H, R248Q, R273C. In this thesis, we have tried to study studied the biophysical aspects of p53 protein mutations using molecular dynamics (MD) studies. All simulation by the help of were performed with the GROMACS (version 5.0.4) package. and Each mutant system was prepared with the SPDVview (version 4-10). In this study, we We have focused on the DNA binding dimer domains of p53 structure. A number of eight simulations were performed using dimer structure of DNA binding domain. we perform a MD simulation of the p53 dimer wild- type p53 and different mutants as R273H, R248W (DNA contact mutations) and R175H, G245S (conformational mutations) versions of the p53 protein, individually separately and in combination with each otherstates. The results of this study showed that the point Changes resulting from this mutations caused different structural effects on the A and B chains of protein although they are homodimmer. doesnt have a uniform impact on the structure of protein in the both chains. Since, the protein's B chain is closer to DNA and easily interacts with DNA that culminated in higher structural stability of B chain against point mutations effects. Data indicated that the mutations have synergetic effects on the protein's conformation, since using four different mutations of R273H, R248W , R175H, G245S in concomitant, resulted in higher proteins structural changes. According to the results, these changes in chain A stronger and more volatility. Which could be due to this fact that the B chain is closer to DNA than A chain and the Interactions between proteins and DNA in the B chain prevent large changes in this chain. Computed data indicate that all mutations in the p53 protein cause energy instability in protein conformation. The study of mutations in combination with each other shows more tangible changes in protein structure and the Sustainable Energy Compared with the impact of the individual mutation. From the data obtained, we can conclude that the conserved domain of this protein is highly sensitive to anythe smallest changes in secondary structure, protein stability and, residues' flexibility. So that Consequently, any possible structural small changes by point mutations cause to appearance of malfunction in the action of p53 such aschanges in the interaction of this protein with other proteins and DNA, Resulting resulting in a change in cell fate and cancer risk
نام شخص به منزله سر شناسه - (مسئولیت معنوی درجه اول )
مستند نام اشخاص تاييد نشده
سعادت علی قیالو، صدیقه
نام شخص - ( مسئولیت معنوی درجه دوم )
مستند نام اشخاص تاييد نشده
برزگر، ابوالفضل، استاد راهنما
مستند نام اشخاص تاييد نشده
مهنام، کریم، استاد مشاور
دسترسی و محل الکترونیکی
يادداشت عمومي
سیاه و سفید
وضعیت فهرست نویسی
وضعیت فهرست نویسی
نمایه‌سازی قبلی
