Whole cell simulator (WCS) aims to provide a computational environment for simulating a whole cell model (WCM). WCM is a comprehensive multi-scale computational model representing all the known biochemical processes in a cell. It relies on a variety of intracellular pathway models and omics data.

The technical objective is to enable seamless integration of diverse simulation methods used in WCM such as stochastic simulation algorithm (SSA), ordinary differential equations (ODE), flux balance analysis (FBA), and logic-based approaches. Currently, WCS implements SSA only, making progress towards achieving this goal. These methods can run simultaneously, not only for whole pathways but also for subsets of reactions. Furthermore, we aim to enable switching dynamically between the methods when beneficial.

• Platforms targeted: Linux-based systems

• c++ compiler that supports c++17 e.g., clang++ 5.0 or later, g++ 7.1 or later, and icpc 19.0.1 or later

• GNU Boost library The particular boost libraries used are graph, filesystem, regex and system. To build with other pre-existing installation of boost, set the environment variable BOOST_ROOT or pass -DBOOST_ROOT=<path-to-boost> to cmake. An example path to boost on LC is /usr/tce/packages/boost/boost-1.69.0-mvapich2-2.3-gcc-8.1.0. To run the executable, add ${BOOST_ROOT}/lib to the LD_LIBRARY_PATH as needed

• Guide specific to using clang on Livermore Computing (LC) platforms Currently, to use clang on Livermore Computing (LC) platforms with the libraries compiled with gcc, make sure the c++ standard library is compatible. On LC, clang by default is paired with c++ standard library from gcc/4.9.3. To avoid incompatibility issue,

  0. Use the user libraries compiled with the system default compiler. On many of LC platforms, it is currently gcc/4.9.3. On others, it depends on how clang is configure there.
  1. Make clang use the c++ standard library from the same version of gcc as that used for building user libraries to link. e.g., clang++ --gcc-toolchain=/usr/tce/packages/gcc/gcc-8.1.0/ ...
  2. Use clang's c++ standard library. Recompile user libraries in the same way as needed. i.e., clang++ --stdlib=libc++ ...

  Choose either USE_GCC_LIBCXX for option 1 or USE_CLANG_LIBCXX for option 2 if needed. Usually, option 1 works best. Option 0 does not work well especially with Catch2 due to the incomplete support for C++17. If neither is chosen, the build relies on the system default, which is, on LC, with USE_GCC_LIBCXX on and GCC_TOOLCHAIN_VER set to "4.9.3". If both are on, USE_GCC_LIBCXX is turned off. When USE_GCC_LIBCXX is on, GCC_TOOLCHAIN_VER can be set accordingly (e.g., "8.1.0"). To make sure to use the correct compiler, invoke the cmake command as CC=clang CXX=clang++ cmake ....

• Guide specific to using the intel compiler on Livermore Computing (LC) platforms

  For gcc Interoperability, use -DGCC_PATH=<path-to-gcc>. Otherwise, icc picks up the gcc in default path, which may not support c++17. Finally, invoke the cmake command as CC=icc CXX=icpc cmake ....

• cmake 3.12 or later

  This requirement mostly comes from the compatibility between the cmake module find_package(), and the version of boost used. An older version might still work with some warnings.

• Cereal

  We rely on Cereal serialization library to enable state packing and unpacking of which needs arises under various circumstances including messaging, rollback, migration, and checkpointing. Cereal is a c++ header-only library. No pre-installation is required as it is automatically downloaded and made available.

• iheap

  We rely on iheap, the indexed-heap library, to implement the next reaction method. This is a header-only library consists of a single file. No pre-installation is required as it is automatically downloaded and made available.

• Protocol Buffers

  We use the google protocol buffers library for parsing the configuration file of simulation, which is written by users in the protocol buffers language. This is a required package. A user can indicate the location of a pre-installed copy via -DPROTOBUF_ROOT=<path>. Without it, building WCS consists of two stages. In the first stage, the source of protocol buffer will be downloaded. Then, the library as well as the protoc compiler will be built and installed under where the rest of WCS project will be. In the second stage, the WCS project will be built using the protocol buffer installed in the first stage. Both stages require the same set of options for the cmake command. In case of cross-compiling, the path to the protoc compiler and the path to the library built for the target platform can be explicitly specified via -DProtobuf_PROTOC_EXECUTABLE=<installation-for-host/bin/protoc> and -DPROTOBUF_DIR=<installation-for-target> respectively.

• libSBML C++ API

  WCS accepts model inputs in SBML format. An input model contains MathML- based description of reaction formula. WCS relies on libSBML to parse the formula, then generates c++ code that includes callable functions of the formula, which is then compiled and linked on-line. To enable SBML-based ingestion, set the environment variable WCS_WITH_SBML or invoke cmake command with the option -DWCS_WITH_SBML:BOOL=ON. The libSBML needs to be pre-instealled before building WCS. The location of the library can be specified either by the environment variable SBML_ROOT or via the cmake option -DSBML_ROOT=<path-to-libsbml>.

git clone https://github.com/llnl/wcs.git
mkdir build; cd build
# The first invocation of cmake will setup to build protocol buffer
cmake -DBOOST_ROOT:PATH=<PathToYourBoostDev> \
      -DCMAKE_INSTALL_PREFIX:PATH=<YourInstallPath> \
      -DWCS_WITH_SBML:BOOL=ON \
      -DSBML_ROOT:PATH=<path-to-libsbml> \
      ../wcs
make -j 4
# The second invocation of cmake will setup to build the WCS project
cmake -DBOOST_ROOT:PATH=<PathToYourBoostDev> \
      -DCMAKE_INSTALL_PREFIX:PATH=<YourInstallPath> \
      -DWCS_WITH_SBML:BOOL=ON \
      -DSBML_ROOT:PATH=<path-to-libsbml> \
      ../wcs
make -j 4
make install

• ExprTK When ExprTk is enabled, WCS relies on ExprTk instead of JIT for generating the functions to compute reaction rates. Once it parses the SBML-based input model using libSBML, it internally constructs formula strings conforming to the expression syntax of ExprTk, which generates callable functions in the form of the abstract syntax tree. To enable ExprTk, use the environment variable WCS_WITH_EXPRTK, or use the cmake option -DWCS_WITH_EXPRTK:BOOL=ON. No pre-installation of ExprTk is required as it will be automatically downloaded while building WCS if the presence is not detected. To use a pre-installed copy regardless, use the environment variable EXPRTK_ROOT or pass it to cmake command as -DEXPRTK_ROOT=<path-to-exprtk>.

• Metis WCS rely on Metis graph partitioning library to perform initial partitioning of reaction network for parallel execution. The partitioning outcome will further be refined by custom algorithm. To link with Metis, use the cmake options -DWCS_WITH_METIS=ON and -DMETIS_ROOT=<path-to-metis-install>.

• Build WCS with the cmake option -DWCS_WITH_OPENMP:BOOL=ON. Then, for accelerating execution performance, use the OpenMP environment variables to control the parallelism and the processor affinity, such as OMP_NUM_THREADS, OMP_PROC_BIND, and OMP_PLACES. Currently, only the next reaction method is parallelized using OpenMP. There are multiple regions where OpenMP parallelization is applied. Use the cmake option -DWCS_OMP_MODE=[1-5] to enable parallelization of a particular combination of regions. The mode 1, 2, and 3 enables fine-grained parallelizaion. The mode 4 and 5 enables the parallelism by partitioning the reaction network.
• Mode 1 helps when there exists a large number of interdependent reactions. In other words, firing a reaction leads to updating a large number of other reactions dependent on the species updated by the reaction fired.
• Mode 2 considers an additional case of a large number of reactants per reactions in addition to parallelizing the same region as the mode 1.
• Mode 3 further addresses an additional case of a large number of products per reaction on top of the parallelization with mode 2.
• Mode 4 implements the parallelization using graph partitioning. This mode is likely to be suitable for a broader range of problems, especially when the size of network is not small. However, currently Metis is required for these.
• Mode 5 combines Mode 1 and Mode 4.

• By default, the type of the variable representing a species copy number is defined as the 32-bit unsigned integer. To enable 64-bit counter, build WCS using the cmake option -DWCS_64BIT_CNT:BOOL=ON.

• Charm++ and Charades (ROSS over Charm++)
• Sundial CVODE For linking with CVODES of Sundials package, use -DWCS_WITH_SUNDIALS:BOOL=ON and -DSUNDIALS_ROOT:FILEPATH=<path-to-sundials>. Make sure that Sundials is built with the cmake option -DBUILD_CVODE:BOOL=ON.

• Catch2 We rely on Catch2 for unit testing. To enable testing for development, set the environment variable WCS_WITH_UNIT_TESTING or invoke cmake with the option -DWCS_WITH_UNIT_TESTING=ON. No pre-installation of Catch2 is required as it is automatically downloaded and made available. To use a pre-installed copy, use the variable CATCH2_ROOT.

Many thanks go to WCS's contributors.

• Jae-Seung Yeom
• Konstantia Georgouli
• Giorgis Georgakoudis
• Robert Blake
• Ali Navid

Whole cell simulator is distributed under the terms of the MIT license. All new contributions must be made under this license. See LICENSE and NOTICE for details.

• SPDX-License-Identifier: MIT
• LLNL-CODE-809742

Please submit any bugfixes or feature improvements as pull requests.