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تسجيل مستخدم جديدStatistical Characterization of a 1D Random Potential Problem - with applications in score statistics of MS-based peptide sequencing
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We provide a complete thermodynamic solution of a 1D hopping model in the presence of a random potential by obtaining the density of states. Since the partition function is related to the density of states by a Laplace transform, the density of states determines completely the thermodynamic behavior of the system. We have also shown that the transfer matrix technique, or the so-called dynamic programming, used to obtain the density of states in the 1D hopping model may be generalized to tackle a long-standing problem in statistical significance assessment for one of the most important proteomic tasks - peptide sequencing using tandem mass spectrometry data.
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Statistically meaningful comparison/combination of peptide identification results from various search methods is impeded by the lack of a universal statistical standard. Providing an E-value calibration protocol, we demonstrated earlier the feasibili
ty of translating either the score or heuristic E-value reported by any method into the textbook-defined E-value, which may serve as the universal statistical standard. This protocol, although robust, may lose spectrum-specific statistics and might require a new calibration when changes in experimental setup occur. To mitigate these issues, we developed a new MS/MS search tool, RAId_aPS, that is able to provide spectrum-specific E-values for additive scoring functions. Given a selection of scoring functions out of RAId score, K-score, Hyperscore and XCorr, RAId_aPS generates the corresponding score histograms of all possible peptides using dynamic programming. Using these score histograms to assign E-values enables a calibration-free protocol for accurate significance assignment for each scoring function. RAId_aPS features four different modes: (i) compute the total number of possible peptides for a given molecular mass range, (ii) generate the score histogram given a MS/MS spectrum and a scoring function, (iii) reassign E-values for a list of candidate peptides given a MS/MS spectrum and the scoring functions chosen, and (iv) perform database searches using selected scoring functions. In modes (iii) and (iv), RAId_aPS is also capable of combining results from different scoring functions using spectrum-specific statistics. The web link is http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/raid_aps/index.html. Relevant binaries for Linux, Windows, and Mac OS X are available from the same page.
Summary: In anticipation of the individualized proteomics era and the need to integrate knowledge from disease studies, we have augmented our peptide identification software RAId DbS to take into account annotated single amino acid polymorphisms, pos
t-translational modifications, and their documented disease associations while analyzing a tandem mass spectrum. To facilitate new discoveries, RAId DbS allows users to conduct searches permitting novel polymorphisms. Availability: The webserver link is http://www.ncbi.nlm.nih.gov/ /CBBResearch/qmbp/raid dbs/index.html. The relevant databases and binaries of RAId DbS for Linux, Windows, and Mac OS X are available from the same web page. Contact: [email protected]
An unsolved challenge in the development of antigen specific immunotherapies is determining the optimal antigens to target. Comprehension of antigen-MHC binding is paramount towards achieving this goal. Here, we present CASTELO, a combined machine le
arning-molecular dynamics (ML-MD) approach to design novel antigens of increased MHC binding affinity for a Type 1 diabetes (T1D)-implicated system. We build upon a small molecule lead optimization algorithm by training a convolutional variational autoencoder (CVAE) on MD trajectories of 48 different systems across 4 antigens and 4 HLA serotypes. We develop several new machine learning metrics including a structure-based anchor residue classification model as well as cluster comparison scores. ML-MD predictions agree well with experimental binding results and free energy perturbation-predicted binding affinities. Moreover, ML-MD metrics are independent of traditional MD stability metrics such as contact area and RMSF, which do not reflect binding affinity data. Our work supports the role of structure-based deep learning techniques in antigen specific immunotherapy design.
Given the emerging global threat of antimicrobial resistance, new methods for next-generation antimicrobial design are urgently needed. We report a peptide generation framework PepCVAE, based on a semi-supervised variational autoencoder (VAE) model,
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The development of single-cell technologies provides the opportunity to identify new cellular states and reconstruct novel cell-to-cell relationships. Applications range from understanding the transcriptional and epigenetic processes involved in meta
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