Publication: Computational dynamical characterization of human major histocompatibility complex proteins
Abstract
Büyük Doku Uygunluk Kompleksi (Majör Histokompatibilite Kompleksi, MHC, veya İnsan Lökosit Antijeni, HLA, olarak da anlandırılır), kısa peptide dizilerini yakalayıp,sitotoksik T hücre lenfositlerine sunarak immün sistemimizde kritik bir rol oynar. MHC proteininin HLA zinciri, aynı zamanda insanlardaki en polimorfik proteindir: insanpopülasyonları arasında ve bireyden bireye en yüksek seviyede farklılık gösteren proteindir. Kaçınılmaz olarak, çok sayıda otoimmün ve enfeksiyon hastalığı ile de ilişkilidir. HLA polimorfizminin işlevsel sonuçlarını anlamak amacıyla, çeşitli simülasyon yöntemlerinin kullanıldığı hesapsal yaklaşımlar yaygınlıkla kullanılmaktadır. Bu tez çalışması, HLA proteinlerinde hesaplamalı biyofizik yöntemleri kullanılarak yapılan araştırma sonuçlarını bir kaç alt başlık altında sunmaktadır. İlk olarak, Ankilozan Spondilit (AS) ile ilişkili olan iki HLA aleli (HLA-B*27:05 ve HLA-B*27:09) arasında asidik ve nötr ortamdaki peptit bağlama davranışları karşılaştırmalı olarak incelenmiş, HLA-B*27:05’nin asidik pH’ya daha duyarlı olduğu gözlenmiştir. İkinci başlık altında, adı geçen iki alelin dinamik davranışı klasik Moleküler Dinamik (MD) simülasyonları kullanılarak karşılaştırılmıştır. Sonuçlar, iki aleli ayırt eden D116H polimorfizminin etkilerinin tüm MHC yapısında yayılarak, peptit sunumu ve eşreseptör etkileşime olası etkilerinin olabileceğini göstermiştir. Üçüncü başlık altında,biyomoleküllerde yerel gerilim konsepti kullanılarak, dizi korunumu/ değişkenliği çerçevesinde HLA polimorfizminin genel bir karakterizasyonu yapılmış, MHC yapısının yüksek polimorfizm seviyesine karşın nasıl korunduğu ortaya konmuştur. Ayrıca, farklı gen bölgelerinden kodlanan MHC molekülleri arasında biyofizik temelli bir farklılık gözlenmiştir. Dördüncü başlık altında, yönlendirilmiş MD simülasyon yöntemi (sMD), HLA-A*02:01 aleline olan bağlanma ilginliğine göre peptitlerin sıralaması için uyarlanmıştır. Son olarak, klasik MD simülasyonlarının analizi için geliştirilmiş olan bir yazılım, protein MD simülasyon gidişizlerinin amino asit etkileşim enerjileri hesaplanarak analiz edilebilmesi amacıyla geliştirilmiştir.
The Major Histocompatibility Complex (MHC, also named Human Leukocyte Antigen, HLA), plays a crucial role in our immune system by capturing and presenting shortpeptides arising from either foreign or self proteins in our bodies to cytotoxic T-lymphocytes. The HLA chains of the MHC is also the most polymorphic protein in humans, showing the highest level of variation between human populations and among individuals. Unsurprisingly, it is also associated with a high number of autoimmune and infectious diseases. With the aim of understanding the functional consequences of the polymorphism, the MHC is studied in the literature extensively via computational approaches using various simulation methods. This thesis work mainly presents results of research conducted on human MHC using computational biophysics methods under several sub-topics. First, the difference between an Ankylosing Spondylitis (AS) associated HLA allele (HLA-B*27:05) and a non-AS-associated one (HLA-B*27:09) was investigated in terms of their peptide binding capacities under acidic versus neutral pH, showing a higher sensitivity of the peptide binding capacity of HLA-B*27:05 to acidic pH levels. Second, these two alleles were studied comparatively in classical MD simulations. The results point to possibly allosteric effects of the D116H polymorphism (differentiating the two alleles) on the whole peptide-loaded MHC (pMHC) structure, with possible implications for peptide presentation as well as co-receptor interactions. Third, an overall structural characterization of the HLA polymorphism is presented using the concept of local frustration in biomolecules in the context of sequence conservation/ variability, explaining how the MHC evolves to maintain its structure despite the high level of variation, in addition to providing a biophysical basis between alleles from different loci. Fourth, an alternative structural simulation method, steered MD simulation, was adapted for binding affinity based ranking of peptides to another well-studied HLA allele (HLA-A*02:01) with general applicability to any peptide protein interaction. Finally, a practical software tool for interaction energy-based analysis of protein MD simulation trajectories, developed as part of the effort in analysis conducted MD simulations, is also presented.
The Major Histocompatibility Complex (MHC, also named Human Leukocyte Antigen, HLA), plays a crucial role in our immune system by capturing and presenting shortpeptides arising from either foreign or self proteins in our bodies to cytotoxic T-lymphocytes. The HLA chains of the MHC is also the most polymorphic protein in humans, showing the highest level of variation between human populations and among individuals. Unsurprisingly, it is also associated with a high number of autoimmune and infectious diseases. With the aim of understanding the functional consequences of the polymorphism, the MHC is studied in the literature extensively via computational approaches using various simulation methods. This thesis work mainly presents results of research conducted on human MHC using computational biophysics methods under several sub-topics. First, the difference between an Ankylosing Spondylitis (AS) associated HLA allele (HLA-B*27:05) and a non-AS-associated one (HLA-B*27:09) was investigated in terms of their peptide binding capacities under acidic versus neutral pH, showing a higher sensitivity of the peptide binding capacity of HLA-B*27:05 to acidic pH levels. Second, these two alleles were studied comparatively in classical MD simulations. The results point to possibly allosteric effects of the D116H polymorphism (differentiating the two alleles) on the whole peptide-loaded MHC (pMHC) structure, with possible implications for peptide presentation as well as co-receptor interactions. Third, an overall structural characterization of the HLA polymorphism is presented using the concept of local frustration in biomolecules in the context of sequence conservation/ variability, explaining how the MHC evolves to maintain its structure despite the high level of variation, in addition to providing a biophysical basis between alleles from different loci. Fourth, an alternative structural simulation method, steered MD simulation, was adapted for binding affinity based ranking of peptides to another well-studied HLA allele (HLA-A*02:01) with general applicability to any peptide protein interaction. Finally, a practical software tool for interaction energy-based analysis of protein MD simulation trajectories, developed as part of the effort in analysis conducted MD simulations, is also presented.