ИСТИНА 
Войти в систему Регистрация 

Интеллектуальная Система Тематического Исследования НАукометрических данных 

The Tcell receptor (TCR) recognizes an antigenic peptide presented by MHC molecule (pMHC). Molecular modeling of ternary TCRpMHC complexes (TC) makes it possible to distinguish antigenic epitopes by computing dG/SASA across the dissociation interface. The computational study used data for the specificity of a set of neoantigenreactive Tlymphocytes obtained using TetTCRseq approach.[1] Methods. All energy estimates were made using REF2015 score function [2]. Models of Tcell receptors were obtained using TCRmodel, and models for epitopes buried into HLAA*02 were built by minimizing Levenstein's distance across PDB using RosettaCM framework. We performed docking in PatchDock and 5 best scoring poses for each TC were consequently refined and mutated using FastRelax and FastDesign. We computed ddG(2) (when mutating the 6 central amino acids to Ala) across each 5 models for a TC and used the largest for analysis. 1. dG = (ETCR + EpMHC  ETCRpMHC)/dSASA, [REU/nm2] 2. ddG = dG6*A  dGWT 3. d = ddGB  ddGNB • H0: There is no difference, on average, between the change in TCRpMHC dissociation energy upon mutation of central positions of an epitope to alanines for models of TC complexed with native and random epitopes. (H0: d = 0) • H1: Models of native TCs change their dissociation energy more strongly when their binding epitope is mutated to alanine in comparison to TC with random nonbinding peptides. (H1: d> 0) Results. When the binding epitope was replaced by a random one, the relative difference in changes in dissociation energies upon mutation of central positions into alanines was μd=7.209 × 102 REU/nm2, 95% CI [3.938 × 102, 1.047 × 101], σd=2.03 × 101, Cohen's d=0.4. The value of the paired onesided ttest is t(200)=4.35 and p =1.1 × 105, hence the hypothesis can be rejected. Conclusion. We show here that the modeling approach is able to distinguish between models of Tcell receptors in complex with binder and nonbinder antigenic epitopes. The further research will examine effect of increased conformational sampling. The Tcell receptor (TCR) recognizes an antigenic peptide presented by MHC molecule (pMHC). Molecular modeling of ternary TCRpMHC complexes (TC) makes it possible to distinguish antigenic epitopes by computing dG/SASA across the dissociation interface. The computational study used data for the specificity of a set of neoantigenreactive Tlymphocytes obtained using TetTCRseq approach.[1] Methods. All energy estimates were made using REF2015 score function [2]. Models of Tcell receptors were obtained using TCRmodel, and models for epitopes buried into HLAA*02 were built by minimizing Levenstein's distance across PDB using RosettaCM framework. We performed docking in PatchDock and 5 best scoring poses for each TC were consequently refined and mutated using FastRelax and FastDesign. We computed ddG(2) (when mutating the 6 central amino acids to Ala) across each 5 models for a TC and used the largest for analysis. 1. dG = (ETCR + EpMHC  ETCRpMHC)/dSASA, [REU/nm2] 2. ddG = dG6*A  dGWT 3. d = ddGB  ddGNB H0: There is no difference, on average, between the change in TCRpMHC dissociation energy upon mutation of central positions of an epitope to alanines for models of TC complexed with native and random epitopes. (H0: d = 0) H1: Models of native TCs change their dissociation energy more strongly when their binding epitope is mutated to alanine in comparison to TC with random nonbinding peptides. (H1: d> 0) Results. When the binding epitope was replaced by a random one, the relative difference in changes in dissociation energies upon mutation of central positions into alanines was μd=7.209 × 102 REU/nm2, 95% CI [3.938 × 102, 1.047 × 101], σd=2.03 × 101, Cohen's d=0.4. The value of the paired onesided ttest is t(200)=4.35 and p =1.1 × 105, hence the hypothesis can be rejected. Conclusion. We show here that the modeling approach is able to distinguish between models of Tcell receptors in complex with binder and nonbinder antigenic epitopes. The further research will examine effect of increased conformational sampling.