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Differentiable Programming of Indexed Chemical Reaction Networks and Reaction-Diffusion Systems

Authors: Inhoo Lee, Salvador Buse, and Erik Winfree

Published in: LIPIcs, Volume 347, 31st International Conference on DNA Computing and Molecular Programming (DNA 31) (2025)

Abstract

Many molecular systems are best understood in terms of prototypical species and reactions. The central dogma and related biochemistry are rife with examples: gene i is transcribed into RNA i, which is translated into protein i; kinase n phosphorylates substrate m; protein p dimerizes with protein q. Engineered nucleic acid systems also often have this form: oligonucleotide i hybridizes to complementary oligonucleotide j; signal strand n displaces the output of seesaw gate m; hairpin p triggers the opening of target q. When there are many variants of a small number of prototypes, it can be conceptually cleaner and computationally more efficient to represent the full system in terms of indexed species (e.g. for dimerization, M_p, D_pq) and indexed reactions (M_p + M_q → D_pq). Here, we formalize the Indexed Chemical Reaction Network (ICRN) model and describe a Python software package designed to simulate such systems in the well-mixed and reaction-diffusion settings, using a differentiable programming framework originally developed for large-scale neural network models, taking advantage of GPU acceleration when available. Notably, this framework makes it straightforward to train the models’ initial conditions and rate constants to optimize a target behavior, such as matching experimental data, performing a computation, or exhibiting spatial pattern formation. The natural map of indexed chemical reaction networks onto neural network formalisms provides a tangible yet general perspective for translating concepts and techniques from the theory and practice of neural computation into the design of biomolecular systems.

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Inhoo Lee, Salvador Buse, and Erik Winfree. Differentiable Programming of Indexed Chemical Reaction Networks and Reaction-Diffusion Systems. In 31st International Conference on DNA Computing and Molecular Programming (DNA 31). Leibniz International Proceedings in Informatics (LIPIcs), Volume 347, pp. 4:1-4:23, Schloss Dagstuhl – Leibniz-Zentrum für Informatik (2025)

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@InProceedings{lee_et_al:LIPIcs.DNA.31.4,
  author =	{Lee, Inhoo and Buse, Salvador and Winfree, Erik},
  title =	{{Differentiable Programming of Indexed Chemical Reaction Networks and Reaction-Diffusion Systems}},
  booktitle =	{31st International Conference on DNA Computing and Molecular Programming (DNA 31)},
  pages =	{4:1--4:23},
  series =	{Leibniz International Proceedings in Informatics (LIPIcs)},
  ISBN =	{978-3-95977-399-7},
  ISSN =	{1868-8969},
  year =	{2025},
  volume =	{347},
  editor =	{Schaeffer, Josie and Zhang, Fei},
  publisher =	{Schloss Dagstuhl -- Leibniz-Zentrum f{\"u}r Informatik},
  address =	{Dagstuhl, Germany},
  URL =		{https://drops.dagstuhl.de/entities/document/10.4230/LIPIcs.DNA.31.4},
  URN =		{urn:nbn:de:0030-drops-238534},
  doi =		{10.4230/LIPIcs.DNA.31.4},
  annote =	{Keywords: Differentiable Programming, Chemical Reaction Networks, Reaction-Diffusion Systems}
}

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Invited Talk

DOI: 10.4230/LIPIcs.FSCD.2025.1

Computation First: Rebuilding Constructivism with Effects (Invited Talk)

Authors: Liron Cohen

Published in: LIPIcs, Volume 337, 10th International Conference on Formal Structures for Computation and Deduction (FSCD 2025)

Abstract

Constructive logic and type theory have traditionally been grounded in pure, effect-free model of computation. This paper argues that such a restriction is not a foundational necessity but a historical artifact, and it advocates for a broader perspective of effectful constructivism, where computational effects, such as state, non-determinism, and exceptions, are directly and internally embedded in the logical and computational foundations. We begin by surveying examples where effects reshape logical principles, and then outline three approaches to effectful constructivism, focusing on realizability models: Monadic Combinatory Algebras, which extend classical partial combinatory algebras with effectful computation; Evidenced Frames, a flexible semantic structure capable of uniformly capturing a wide range of effects; and Effectful Higher-Order Logic (EffHOL), a syntactic approach that directly translates logical propositions into specifications for effectful programs. We further illustrate how concrete type theories can internalize effects, via the family of type theories TT^□_C. Together, these works demonstrate that effectful constructivism is not merely possible but a natural and robust extension of traditional frameworks.

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Liron Cohen. Computation First: Rebuilding Constructivism with Effects (Invited Talk). In 10th International Conference on Formal Structures for Computation and Deduction (FSCD 2025). Leibniz International Proceedings in Informatics (LIPIcs), Volume 337, pp. 1:1-1:20, Schloss Dagstuhl – Leibniz-Zentrum für Informatik (2025)

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@InProceedings{cohen:LIPIcs.FSCD.2025.1,
  author =	{Cohen, Liron},
  title =	{{Computation First: Rebuilding Constructivism with Effects}},
  booktitle =	{10th International Conference on Formal Structures for Computation and Deduction (FSCD 2025)},
  pages =	{1:1--1:20},
  series =	{Leibniz International Proceedings in Informatics (LIPIcs)},
  ISBN =	{978-3-95977-374-4},
  ISSN =	{1868-8969},
  year =	{2025},
  volume =	{337},
  editor =	{Fern\'{a}ndez, Maribel},
  publisher =	{Schloss Dagstuhl -- Leibniz-Zentrum f{\"u}r Informatik},
  address =	{Dagstuhl, Germany},
  URL =		{https://drops.dagstuhl.de/entities/document/10.4230/LIPIcs.FSCD.2025.1},
  URN =		{urn:nbn:de:0030-drops-236167},
  doi =		{10.4230/LIPIcs.FSCD.2025.1},
  annote =	{Keywords: Effectful constructivism, realizability, type theory, monadic combinatory algebras, evidenced frame}
}

Document

DOI: 10.4230/LIPIcs.ECOOP.2025.12

Automatic Goal Clone Detection in Rocq

Authors: Ali Ghanbari

Published in: LIPIcs, Volume 333, 39th European Conference on Object-Oriented Programming (ECOOP 2025)

Abstract

Proof engineering in Rocq is a labor-intensive process, and as proof developments grow in size, redundancy and maintainability become challenges. One such redundancy is goal cloning, i.e., proving α-equivalent goals multiple times, leading to wasted effort and bloated proof scripts. In this paper, we introduce clone-finder, a novel technique for detecting goal clones in Rocq proofs. By leveraging the formal notion of α-equivalence for Gallina terms, clone-finder systematically identifies duplicated proof goals across large Rocq codebases. We evaluate clone-finder on 40 real-world Rocq projects from the CoqGym dataset. Our results reveal that each project contains an average of 27.73 instances of goal clone. We observed that the clones can be categorized as either exact goal duplication, generalization, or α-equivalent goals with different proofs, each signifying varying levels duplicate effort. Our findings highlight significant untapped potential for proof reuse in Rocq-based formal verification projects, paving the way for future improvements in automated proof engineering.

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Ali Ghanbari. Automatic Goal Clone Detection in Rocq. In 39th European Conference on Object-Oriented Programming (ECOOP 2025). Leibniz International Proceedings in Informatics (LIPIcs), Volume 333, pp. 12:1-12:19, Schloss Dagstuhl – Leibniz-Zentrum für Informatik (2025)

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@InProceedings{ghanbari:LIPIcs.ECOOP.2025.12,
  author =	{Ghanbari, Ali},
  title =	{{Automatic Goal Clone Detection in Rocq}},
  booktitle =	{39th European Conference on Object-Oriented Programming (ECOOP 2025)},
  pages =	{12:1--12:19},
  series =	{Leibniz International Proceedings in Informatics (LIPIcs)},
  ISBN =	{978-3-95977-373-7},
  ISSN =	{1868-8969},
  year =	{2025},
  volume =	{333},
  editor =	{Aldrich, Jonathan and Silva, Alexandra},
  publisher =	{Schloss Dagstuhl -- Leibniz-Zentrum f{\"u}r Informatik},
  address =	{Dagstuhl, Germany},
  URL =		{https://drops.dagstuhl.de/entities/document/10.4230/LIPIcs.ECOOP.2025.12},
  URN =		{urn:nbn:de:0030-drops-233055},
  doi =		{10.4230/LIPIcs.ECOOP.2025.12},
  annote =	{Keywords: Clone Detection, Goal, Proof, Rocq, Gallina}
}

Document

DOI: 10.4230/LIPIcs.ECOOP.2025.10

Bottom-Up Synthesis of Memory Mutations with Separation Logic

Authors: Kasra Ferdowsi and Hila Peleg

Published in: LIPIcs, Volume 333, 39th European Conference on Object-Oriented Programming (ECOOP 2025)

Abstract

Programming-by-Example (PBE) is the paradigm of program synthesis specified via input-output pairs. It is commonly used because examples are easy to provide and collect from the environment. A popular optimization for enumerative synthesis with examples is Observational Equivalence (OE), which groups programs into equivalence classes according to their evaluation on example inputs. Current formulations of OE, however, are severely limited by the assumption that the synthesizer’s target language contains only pure components with no side-effects, either enforcing this in their target language, or ignoring it, leading to an incorrect enumeration. This limits their ability to use realistic component sets. We address this limitation by borrowing from Separation Logic, which can compositionally reason about heap mutations. We reformulate PBE using a restricted Separation Logic: Concrete Heap Separation Logic (CHSL), transforming the search for programs into a proof search in CHSL. This lets us perform bottom-up enumerative synthesis without the need for expert-provided annotations or domain-specific inferences, but with three key advantages: we (i) preserve correctness in the presence of memory-mutating operations, (ii) compact the search space by representing many concrete programs as one under CHSL, and (iii) perform a provably correct OE-reduction. We present SObEq (Side-effects in OBservational EQuivalence), a bottom-up enumerative algorithm that, given a PBE task, searches for its CHSL derivation. The SObEq algorithm is proved correct with no purity assumptions: we show it is guaranteed to lose no solutions. We also evaluate our implementation of SObEq on benchmarks from the literature and online sources, and show that it produces high-quality results quickly.

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Kasra Ferdowsi and Hila Peleg. Bottom-Up Synthesis of Memory Mutations with Separation Logic. In 39th European Conference on Object-Oriented Programming (ECOOP 2025). Leibniz International Proceedings in Informatics (LIPIcs), Volume 333, pp. 10:1-10:32, Schloss Dagstuhl – Leibniz-Zentrum für Informatik (2025)

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@InProceedings{ferdowsi_et_al:LIPIcs.ECOOP.2025.10,
  author =	{Ferdowsi, Kasra and Peleg, Hila},
  title =	{{Bottom-Up Synthesis of Memory Mutations with Separation Logic}},
  booktitle =	{39th European Conference on Object-Oriented Programming (ECOOP 2025)},
  pages =	{10:1--10:32},
  series =	{Leibniz International Proceedings in Informatics (LIPIcs)},
  ISBN =	{978-3-95977-373-7},
  ISSN =	{1868-8969},
  year =	{2025},
  volume =	{333},
  editor =	{Aldrich, Jonathan and Silva, Alexandra},
  publisher =	{Schloss Dagstuhl -- Leibniz-Zentrum f{\"u}r Informatik},
  address =	{Dagstuhl, Germany},
  URL =		{https://drops.dagstuhl.de/entities/document/10.4230/LIPIcs.ECOOP.2025.10},
  URN =		{urn:nbn:de:0030-drops-233036},
  doi =		{10.4230/LIPIcs.ECOOP.2025.10},
  annote =	{Keywords: Program synthesis, observational equivalence}
}

Document

DOI: 10.4230/LIPIcs.DNA.2020.4

CRNs Exposed: A Method for the Systematic Exploration of Chemical Reaction Networks

Authors: Marko Vasic, David Soloveichik, and Sarfraz Khurshid

Published in: LIPIcs, Volume 174, 26th International Conference on DNA Computing and Molecular Programming (DNA 26) (2020)

Abstract

Formal methods have enabled breakthroughs in many fields, such as in hardware verification, machine learning and biological systems. The key object of interest in systems biology, synthetic biology, and molecular programming is chemical reaction networks (CRNs) which formalizes coupled chemical reactions in a well-mixed solution. CRNs are pivotal for our understanding of biological regulatory and metabolic networks, as well as for programming engineered molecular behavior. Although it is clear that small CRNs are capable of complex dynamics and computational behavior, it remains difficult to explore the space of CRNs in search for desired functionality. We use Alloy, a tool for expressing structural constraints and behavior in software systems, to enumerate CRNs with declaratively specified properties. We show how this framework can enumerate CRNs with a variety of structural constraints including biologically motivated catalytic networks and metabolic networks, and seesaw networks motivated by DNA nanotechnology. We also use the framework to explore analog function computation in rate-independent CRNs. By computing the desired output value with stoichiometry rather than with reaction rates (in the sense that X → Y+Y computes multiplication by 2), such CRNs are completely robust to the choice of reaction rates or rate law. We find the smallest CRNs computing the max, minmax, abs and ReLU (rectified linear unit) functions in a natural subclass of rate-independent CRNs where rate-independence follows from structural network properties.

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Marko Vasic, David Soloveichik, and Sarfraz Khurshid. CRNs Exposed: A Method for the Systematic Exploration of Chemical Reaction Networks. In 26th International Conference on DNA Computing and Molecular Programming (DNA 26). Leibniz International Proceedings in Informatics (LIPIcs), Volume 174, pp. 4:1-4:25, Schloss Dagstuhl – Leibniz-Zentrum für Informatik (2020)

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@InProceedings{vasic_et_al:LIPIcs.DNA.2020.4,
  author =	{Vasic, Marko and Soloveichik, David and Khurshid, Sarfraz},
  title =	{{CRNs Exposed: A Method for the Systematic Exploration of Chemical Reaction Networks}},
  booktitle =	{26th International Conference on DNA Computing and Molecular Programming (DNA 26)},
  pages =	{4:1--4:25},
  series =	{Leibniz International Proceedings in Informatics (LIPIcs)},
  ISBN =	{978-3-95977-163-4},
  ISSN =	{1868-8969},
  year =	{2020},
  volume =	{174},
  editor =	{Geary, Cody and Patitz, Matthew J.},
  publisher =	{Schloss Dagstuhl -- Leibniz-Zentrum f{\"u}r Informatik},
  address =	{Dagstuhl, Germany},
  URL =		{https://drops.dagstuhl.de/entities/document/10.4230/LIPIcs.DNA.2020.4},
  URN =		{urn:nbn:de:0030-drops-129574},
  doi =		{10.4230/LIPIcs.DNA.2020.4},
  annote =	{Keywords: molecular programming, formal methods}
}

Document

DOI: 10.4230/LIPIcs.ECOOP.2018.6

Learning to Accelerate Symbolic Execution via Code Transformation

Authors: Junjie Chen, Wenxiang Hu, Lingming Zhang, Dan Hao, Sarfraz Khurshid, and Lu Zhang

Published in: LIPIcs, Volume 109, 32nd European Conference on Object-Oriented Programming (ECOOP 2018)

Abstract

Symbolic execution is an effective but expensive technique for automated test generation. Over the years, a large number of refined symbolic execution techniques have been proposed to improve its efficiency. However, the symbolic execution efficiency problem remains, and largely limits the application of symbolic execution in practice. Orthogonal to refined symbolic execution, in this paper we propose to accelerate symbolic execution through semantic-preserving code transformation on the target programs. During the initial stage of this direction, we adopt a particular code transformation, compiler optimization, which is initially proposed to accelerate program concrete execution by transforming the source program into another semantic-preserving target program with increased efficiency (e.g., faster or smaller). However, compiler optimizations are mostly designed to accelerate program concrete execution rather than symbolic execution. Recent work also reported that unified settings on compiler optimizations that can accelerate symbolic execution for any program do not exist at all. Therefore, in this work we propose a machine-learning based approach to tuning compiler optimizations to accelerate symbolic execution, whose results may also aid further design of specific code transformations for symbolic execution. In particular, the proposed approach LEO separates source-code functions and libraries through our program-splitter, and predicts individual compiler optimization (i.e., whether a type of code transformation is chosen) separately through analyzing the performance of existing symbolic execution. Finally, LEO applies symbolic execution on the code transformed by compiler optimization (through our local-optimizer). We conduct an empirical study on GNU Coreutils programs using the KLEE symbolic execution engine. The results show that LEO significantly accelerates symbolic execution, outperforming the default KLEE configurations (i.e., turning on/off all compiler optimizations) in various settings, e.g., with the default training/testing time, LEO achieves the highest line coverage in 50/68 programs, and its average improvement rate on all programs is 46.48%/88.92% in terms of line coverage compared with turning on/off all compiler optimizations.

Cite as

Junjie Chen, Wenxiang Hu, Lingming Zhang, Dan Hao, Sarfraz Khurshid, and Lu Zhang. Learning to Accelerate Symbolic Execution via Code Transformation. In 32nd European Conference on Object-Oriented Programming (ECOOP 2018). Leibniz International Proceedings in Informatics (LIPIcs), Volume 109, pp. 6:1-6:27, Schloss Dagstuhl – Leibniz-Zentrum für Informatik (2018)

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@InProceedings{chen_et_al:LIPIcs.ECOOP.2018.6,
  author =	{Chen, Junjie and Hu, Wenxiang and Zhang, Lingming and Hao, Dan and Khurshid, Sarfraz and Zhang, Lu},
  title =	{{Learning to Accelerate Symbolic Execution via Code Transformation}},
  booktitle =	{32nd European Conference on Object-Oriented Programming (ECOOP 2018)},
  pages =	{6:1--6:27},
  series =	{Leibniz International Proceedings in Informatics (LIPIcs)},
  ISBN =	{978-3-95977-079-8},
  ISSN =	{1868-8969},
  year =	{2018},
  volume =	{109},
  editor =	{Millstein, Todd},
  publisher =	{Schloss Dagstuhl -- Leibniz-Zentrum f{\"u}r Informatik},
  address =	{Dagstuhl, Germany},
  URL =		{https://drops.dagstuhl.de/entities/document/10.4230/LIPIcs.ECOOP.2018.6},
  URN =		{urn:nbn:de:0030-drops-92115},
  doi =		{10.4230/LIPIcs.ECOOP.2018.6},
  annote =	{Keywords: Symbolic Execution, Code Transformation, Machine Learning}
}

6 Search Results for "Khurshid, Sarfraz"

Differentiable Programming of Indexed Chemical Reaction Networks and Reaction-Diffusion Systems

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Computation First: Rebuilding Constructivism with Effects (Invited Talk)

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Automatic Goal Clone Detection in Rocq

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Bottom-Up Synthesis of Memory Mutations with Separation Logic

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CRNs Exposed: A Method for the Systematic Exploration of Chemical Reaction Networks

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Learning to Accelerate Symbolic Execution via Code Transformation

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