Toward the atomistic simulation of T cell epitopes automated construction of MHC: peptide structures for free energy calculations
ABSTRACT Epitopes mediated by T cells lie at the heart of the adaptive immune response and form the essential nucleus of anti-tumour peptide or epitope-based vaccines. Antigenic T cell epitopes are mediated by major histocompatibility complex (MHC) molecules, which present them to T cell receptors. Calculating the affinity between a given MHC molecule and an antigenic peptide using experimental approaches is both difficult and time consuming, thus various computational methods have been developed for this purpose. A server has been developed to allow a structural approach to the problem by generating specific MHC:peptide complex structures and providing configuration files to run molecular modelling simulations upon them. A system has been produced which allows the automated construction of MHC:peptide structure files and the corresponding configuration files required to execute a molecular dynamics simulation using NAMD. The system has been made available through a web-based front end and stand-alone scripts. Previous attempts at structural prediction of MHC:peptide affinity have been limited due to the paucity of structures and the computational expense in running large scale molecular dynamics simulations. The MHCsim server (http://igrid-ext.cryst.bbk.ac.uk/MHCsim) allows the user to rapidly generate any desired MHC:peptide complex and will facilitate molecular modelling simulation of MHC complexes on an unprecedented scale.
- SourceAvailable from: Priyanka Chaubey[Show abstract] [Hide abstract]
ABSTRACT: The present work uses a structural simulation approach to identify the potential target vaccine candidates or T cell epitopes (antigenic region that can activate T cell response) in two iron acquisition proteins from Neisseria. An iron regulated outer membrane protein frpB: extracellular, [NMB1988], and a Major ferric Iron-binding protein fbpA: periplasmic, [NMB0634] critical for the survival of the pathogen in the host were used. Ten novel promiscuous epitopes from the two iron acquisition proteins were identified using bioinformatics interface. Of these epitopes, 630VQKAVGSIL638 present on frpB with high binding affinity for allele HLA*DR1 was identified with an anchor position at P2, an aliphatic residue at P4 and glycine at P6 making it thereby a potential quality choice for linking peptide-loaded MHC dynamics to T-cell activation and vaccine constructs. The feasibility and structural binding of predicted peptide to the respective HLA allele was investigated by molecular modeling and template-based structural simulation. The conformational properties of the linear peptide were investigated by molecular dynamics using GROMOS96 package and Swiss PDB viewer.JOURNAL OF PROTEINS AND PROTEOMICS. 01/2010; 1(2):53 – 63.
- [Show abstract] [Hide abstract]
ABSTRACT: Virtual interactomics represents a rapidly developing scientific area on the boundary line of bioinformatics and interactomics. Protein-related virtual interactomics then comprises instrumental tools for prediction, simulation, and networking of the majority of interactions important for structural and individual reproduction, differentiation, recognition, signaling, regulation, and metabolic pathways of cells and organisms. Here, we describe the main areas of virtual protein interactomics, that is, structurally based comparative analysis and prediction of functionally important interacting sites, mimotope-assisted and combined epitope prediction, molecular (protein) docking studies, and investigation of protein interaction networks. Detailed information about some interesting methodological approaches and online accessible programs or databases is displayed in our tables. Considerable part of the text deals with the searches for common conserved or functionally convergent protein regions and subgraphs of conserved interaction networks, new outstanding trends and clinically interesting results. In agreement with the presented data and relationships, virtual interactomic tools improve our scientific knowledge, help us to formulate working hypotheses, and they frequently also mediate variously important in silico simulations.Molecular biology international. 01/2012; 2012:976385.
- [Show abstract] [Hide abstract]
ABSTRACT: The CrossTope is a highly curate repository of three-dimensional structures of peptide:major histocompatibility complex (MHC) class I complexes (pMHC-I). The complexes hosted by this databank were obtained in protein databases and by large-scale in silico construction of pMHC-I structures, using a new approach developed by our group. At this moment, the database contains 182 'non-redundant' pMHC-I complexes from two human and two murine alleles. A web server provides interface for database query. The user can download (i) structure coordinate files and (ii) topological and charges distribution maps images from the T-cell receptor-interacting surface of pMHC-I complexes. The retrieved structures and maps can be used to cluster similar epitopes in cross-reactivity approaches, to analyse viral escape mutations in a structural level or even to improve the immunogenicity of tumour antigens. Database URL: http://www.crosstope.com.br.Database The Journal of Biological Databases and Curation 01/2013; 2013:bat002. · 4.46 Impact Factor