Specificity prediction of adenylation domains in nonribosomal peptide synthetases (NRPS) using transductive support vector machines (TSVMs)

We present a new support vector machine (SVM)-based approach to predict the substrate specificity of subtypes of a given protein sequence family. We demonstrate the usefulness of this method on the example of aryl acid-activating and amino acid-activating adenylation domains (A domains) of nonribosomal peptide synthetases (NRPS). The residues of gramicidin synthetase A that are 8 Å around the substrate amino acid and corresponding positions of other adenylation domain sequences with 397 known and unknown specificities were extracted and used to encode this physico-chemical fingerprint into normalized real-valued feature vectors based on the physico-chemical properties of the amino acids. The SVM software package SVM(light) was used for training and classification, with transductive SVMs to take advantage of the information inherent in unlabeled data. Specificities for very similar substrates that frequently show cross-specificities were pooled to the so-called composite specificities and predictive models were built for them. The reliability of the models was confirmed in cross-validations and in comparison with a currently used sequence-comparison-based method. When comparing the predictions for 1230 NRPS A domains that are currently detectable in UniProt, the new method was able to give a specificity prediction in an additional 18% of the cases compared with the old method. For 70% of the sequences both methods agreed, for <6% they did not, mainly on low-confidence predictions by the existing method. None of the predictive methods could infer any specificity for 2.4% of the sequences, suggesting completely new types of specificity

Interprocedural shape analysis for effectively cutpoint-free programs

Abstract. We present a framework for local interprocedural shape analysis that computes procedure summaries as transformers of procedure-local heaps (the parts of the heap that the procedure may reach). A main challenge in procedurelocal shape analysis is the handling of cutpoints, objects that separate the input heap of an invoked procedure from the rest of the heap, which-from the viewpoint of that invocation-is non-accessible and immutable. In this paper, we limit our attention to effectively cutpoint-free programsprograms in which the only objects that separate the callee&apos;s heap from the rest of the heap, when considering live reference fields, are the ones pointed to by the actual parameters of the invocation. This limitation (and certain variations of it, which we also describe) simplifies the local-reasoning about procedure calls because the analysis needs not track cutpoints. Furthermore, our analysis (conservatively) verifies that a program is effectively cutpoint-free

Chopped symbolic execution

Symbolic execution is a powerful program analysis technique that systematically explores multiple program paths. However, despite important technical advances, symbolic execution often struggles to reach deep parts of the code due to the well-known path explosion problem and constraint solving limitations. In this paper, we propose chopped symbolic execution , a novel form of symbolic execution that allows users to specify uninter- esting parts of the code to exclude during the analysis, thus only targeting the exploration to paths of importance. However, the excluded parts are not summarily ignored, as this may lead to both false positives and false negatives. Instead, they are executed lazily, when their effect may be observable by code under anal- ysis. Chopped symbolic execution leverages various on-demand static analyses at runtime to automatically exclude code fragments while resolving their side effects, thus avoiding expensive manual annotations and imprecision. Our preliminary results show that the approach can effectively improve the effectiveness of symbolic execution in several different scenarios, including failure reproduction and test suite augmenta- tion

Past-sensitive pointer analysis for symbolic execution

We propose a novel fine-grained integration of pointer analysis with dynamic analysis, including dynamic symbolic execution. This is achieved via past-sensitive pointer analysis, an on-demand pointer analysis instantiated with an abstraction of the dynamic state on which it is invoked. We evaluate our technique in three application scenarios: chopped symbolic execution, symbolic pointer resolution, and write integrity testing. Our preliminary results show that the approach can have a significant impact in these scenarios, by effectively improving the precision of standard pointer analysis with only a modest performance overhead