BioExcel supports the development of pmx, a tool for researchers utilising free energy calculations.
Free energy calculations are extremely common in life sciences research. In molecular dynamics simulations, such as investigating how mutations affect protein function, these calculations provide insight into stability and affinity changes.
One important branch of free energy calculations involve alchemical transformations such as the mutation of amino acids, nucleic acids or ligand modifications. A challenging aspect of these calculations is the creation of associated structures and molecular topologies. pmx provides an automated framework for the introduction of amino acid mutations in proteins. Several state of the art force fields are supported that can be used in the GROMACS molecular dynamics package.
With the recent successful launch of the pmx webserver for amino acid mutations, GROMACS users have access to setting up such alchemical molecular dynamics (MD) based mutation free energy calculations without the need to install any additional software. The development of the pmx webserver and the GROMACS software has been partly supported by BioExcel. GROMACS is one of the major codes offered as part of the BioExcel community of services and this development makes it an even more powerful tool for molecular simulations.
An article accompanying these newly introduced online utilities was published in early 2017 to introduce the scientific community to the progress in pmx development. As well as implementing the new web-based features, the core pmx functionality – hybrid structure/topology generation – was also expanded. In addition to the already established ability to process amino acid mutations, pmx was also extended to handle DNA nucleotide alchemical transformations. We have successfully employed the newly developed pmx features in a large scale nucleotide mutation scan over a number of protein-DNA complexes, and a publication describing the results of this investigation is currently in preparation. Additionally, a new, pre-generated tripeptide library (together with the pre-calculated free energy values), mimicking the protein disordered state, facilitates protein stability estimation by means of MD.
Another branch of pmx development comprises alchemical ligand modifications. Having already laid the ground work in this direction, we are planning to release the pmx version capable of atom mapping and hybrid structure/topology generation for arbitrary molecules in 2017.
Development of the pmx webserver as part of the BioExcel Centre of Excellence has thus provided researchers with a powerful tool for alchemical free energy simulations. As part of the BioExcel initiative, we offer a range of support options to pmx users, such as webinars (link) and an upcoming workshop on free energy calculations, organized jointly with the CompBioMed Centre of Excellence. The workshop will bring together the two initiatives (BioExcel and CompBioMed) based on their shared interest in the methodology and application of the molecular dynamics based free energy calculations. The meeting will provide an opportunity to introduce the developed methods and avenues of their potential application to the broader scientific community.