Can one infer the amino acids of the enzymes that are responsible for the stability or the level of the catalytic activity by computationally experimenting on the inhibited enzyme in the enzyme-inhibitor complex? In this article, we answer this question positively both by designing molecular dynamics simulations and by devising coarse-grained methodologies on the subtilisin serine protease. Both methodologies are based on the cross-correlations of the fluctuations of the residues, obtained either by monitoring the trajectories from the simulation or by constructing the inverse Laplacian of the elastic network model, of the complex. A perturbation scanning is applied to the complex using these correlations. The results indicate that the two methods almost point out the same regions on the flexible of the enzyme. These regions are: (i) 50-61, (ii) 155-164 and (iii) 192-194, all of which are designated to be important by experimental studies in the literature.

We have studied the apo (Fe 3+ free) form of periplasmic ferric binding protein (FbpA) under different conditions and we have monitored the changes in the binding and release dynamics of H 2 PO 4 − that acts as a synergistic anion in the presence of Fe 3+ . Our simulations predict a dissociation constant of 2.2±0.2 mM which is in remarkable agreement with the experimentally measured value of 2.3±0.3 mM under the same ionization strength and pH conditions. We apply perturbations relevant for changes in environmental conditions as (i) different values of ionization strength (IS), and (ii) protonation of a group of residues to mimic a different pH environment. Local perturbations are also studied by protonation or mutation of a site distal to the binding region that is known to mechanically manipulate the hinge-like motions of FbpA.We find that while the average conformation of the protein is intact in all simulations, the H 2 PO 4 − dynamics may be substantially altered by the changing conditions. In particular, the bound fraction which is 20% for the wild type system is increased to 50% with a D52A mutation/protonation and further to over 90% at the protonation conditions mimicking those at pH 5.5. The change in the dynamics is traced to the altered electrostatic distribution on the surface of the protein which in turn affects hydrogen bonding patterns at the active site. The observations are quantified by rigorous free energy calculations. Our results lend clues as to how the environment versus single residue perturbations may be utilized for regulation of binding modes in hFbpA systems in the absence of conformational changes. 3 AUTHOR SUMMARYBacterial ferric binding protein A (FbpA) plays a major role in iron confiscation from its host.Phosphate has been long identified as a synergistic anion for iron in this transport protein, while its mode of action is still debated. We have demonstrated in this work that phosphate binding to apo FbpA is a heavily environment dependent activity. Hydrogen-bond network motifs between the phosphate and its surrounding residues in FbpA become more stable when we lower the pH.With the aid of extensive molecular dynamics simulations conducted for different protonation scenarios, we show that the average structure of the protein is not altered during phosphate binding. Despite the lack of conformational transitions, however, phosphate binding-release dynamics is substantially affected by these changes. We find that the charges are redistributed, giving rise to altered fluctuation patterns of the loops remotely controlling the binding activity.

Bu çalışmada, DEHB tanılı çocuk ve ergenlerden oluşan klinik bir örneklemde psikiyatrik komorbidite, uyku problemleri ve bunların DEHB görünümü, yaş ve cinsiyetle olan ilişkilerinin incelenmesi amaçlanmış. Gereç ve Yöntem: Çalışmaya 6-17 yaş arası 154 katılımcı dahil edildi. Psikiyatrik bozuklukları değerlendirmek amacıyla yarı yapılandırılmış bir klinik görüşme gerçekleştirildi. İçselleştirme ve uyku sorunlarını değerlendirmek için Çocuklar için Anksiyete Bozuklukları Tarama Ölçeği (ÇATÖ), Çocuk Depresyon Envanteri (ÇDE) ve Çocuk Uyku Alışkanlıkları Anketi (ÇUAA) kullanıldı. Bulgular: Katılımcılar arasında komorbid hastalık (%78) ve uyku problemleri (%97) sıklıkları oldukça yüksekti. DEHB bileşik görünüm erkeklerde daha sık olarak tespit edildi (p<0,001) ve karşıt olma-karşı gelme bozukluğu, enürezi ve enkoprezi bileşik görünümdeki olgularda daha sıktı (p<0,05). Dikkatsizlik görünümündeki olgularda ise sosyal anksiyete bozukluğu ve yaygın anksiyete bozukluğu görülme sıklıkları bileşik görünümdeki olgulara göre daha fazlaydı (p<0,05). Erkeklerle karşılaştırıldığında, kızlarda sosyal anksiyete bozukluğu (p=0,03) ve depresyon (p=0,021) daha sık olarak görülmekteydi. Katılımcıların %96,7'si ÇUAA'nde kesme puanı olan 41'in üzerinde skora sahipti (50,51±5,86). Bileşik görünümdeki olguların ÇUAA skorları dikkatsizlik görünümündeki olgulardan anlamlı olarak daha yüksekti (p<0,05). ÇUAA skorları ile toplam yaşam boyu psikiyatrik hastalık sayısı ve ABSTRACT Objective: This study aimed to investigate psychiatric comorbidity and sleep problems and their relationships with ADHD presentation, age and gender in a clinical sample of children and adolescents with ADHD. Material and Method: One hundred fifty-four subjects aged 6-17 were included in the study. A semi-structured diagnostic interview was conducted to screen psychiatric disorders. The Child Depression Inventory (CDI), Screen for Child Anxiety Related Emotional Disorders (SCARED) and Children's Sleep Habits Questionnaire (CSHQ) were used to investigate internalizing difficulties and sleep problems. Results: Overall high rates of comorbid disorders (78%) and sleep problems (97%) were found. ADHD-C was significantly more frequent in males and ADHD-I was more frequent in females (p<0.001). While oppositional defiant disorder (ODD), enuresis and encopresis were more frequent in subjects with ADHD-C (p<0.05), generalized anxiety (GAD) and social anxiety (SAD) disorders were more frequent in subjects with ADHD-I (p<0.05). Females, compared to males, had more frequent diagnoses of depression (p=0.021) and SAD (p=0.03). The majority of subjects (96.7%) scored above the cut off score of 41 in CSHQ (50.51±5.86). The ADHD-C group had significantly higher CSHQ total scores than the ADHD-I group (p<0.05). There was a significant positive correlation between CSHQ total scores and the Comorbidity and sleep problems in ADHD İstanbul Tıp Fakültesi Dergisi • J Ist Faculty Med 2020;83(4):363-72 number of lifetime comorbid diagnoses (p=0.006), self-reported anxiety (p=0.009) and depressi...

Long-range information transfer within proteins, specifically from the substrate binding site to a distant surface site, plays a vital role in regulation of its activ-

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