AMBERff with NAMD is implemented by researchers from the University of Delaware to enable simulations of large systems built upon existing software infrastructure. Increasingly used in multimillion-atom systems such as viruses and biological machinery, all-atom molecular dynamics (MD) simulations are a fundamental structural biology approach. The AMBER family of force fields (AMBERff) parameter sets are used in classical MD simulations to represent molecular motion accurately. Case studies on model systems and single-point potential energy comparisons show that the implementation yields results comparable to those obtained using AMBERff in its native engine. Implementing AMBERff with NAMD enables high-performing simulations to handle up to two billion atoms.
Understanding the Importance of MD Simulation and Force Fields
In structural biology, MD simulations are an essential tool that provides features that are not available by experimental methods. They make it possible for scientists to look at limited time scales of biological activity in large-scale biomolecular systems, such as cellular machinery and viruses. In recent years, these simulations have led to ground-breaking findings by integrating data from cryo-electron microscopy and tomography, X-ray crystallography, and NMR spectroscopy.
Atoms and bonds in biomolecular systems are modeled as balls and springs in MD simulations using force fields. These force fields use a molecule’s shape to determine its potential energy. Over time, the system’s configuration changes are driven by the potential energy gradient. Molecular motion is produced by computing millions of steps over time. Force fields that replicate biophysical features and capture realistic dynamics are empirically optimized, tested experimentally, and parameterized. Force field families like AMBERff, CHARMMff, GROMOS, and OPLS are frequently employed to simulate intricate, chemically realistic systems. Research on force field development is still in progress.
Force fields such as AMBER, CHARMM, GROMACS, LAMMPS, and NAMD are utilized in MD simulation software to simulate the motion of biomolecular systems. While NAMD is appropriate for large-scale simulations on leadership-class supercomputers and intermediate-scale simulations on GPU-dense architectures, AMBER’s pmemd.cuda is best suited for small-scale simulations on GPU-accelerated nodes.
Scaling New Heights with NAMD and AMBERff Integration
Multimillion-atom MD simulations can be used to study biologically significant systems, like the macromolecular assemblies that control cellular and viral functions. Large-scale all-atom MD simulations of the HIV-1 capsid, photosynthetic chromatophore organelle, and influenza A virion have been performed using CHARMMff in NAMD. However, due to restrictions in the PRMTOP file format and precalculation values, systems of this magnitude are not possible within the AMBER framework.
The availability of all leading biomolecular force fields within software well-suited for high-performance simulations at a scale is crucial, given the growing efforts in the field to model and simulate large biological systems, including intact viruses and minimal cells with their enclosed genetic material. Thus, the implementation of AMBERff for NAMD allows simulations with a force field family of up to two billion atoms, which is three orders of magnitude larger than what is currently tractable with AMBERff in its native engine. Thus, the researchers present this implementation here. Using the psfgen file builder as a standalone binary and VMD plugin, the NAMD method is simple. By generating PSF and JS molecular topology files without atom count limits, this technique improves potential energy agreement and biophysical qualities and makes it possible to use AMBERff to research biological system dynamics at scale.
This paper presents an integration of AMBERff with NAMD, which is the creation of a robust force field with a powerful simulation engine that can unlock a new frontier in molecular dynamics simulation. The AMBER program can read the PRMTOP file format (created, for example, by tleap) natively and encode the molecular topology and parameter data for AMBERff. Since NAMD can read PRMTOP files natively, precise force field simulations on supercomputers are currently possible. The scientists calibrated the parameters of AMBERff to seamlessly fit into the NAMD framework. The synergy between the two enhances the quality of simulation and also improves the fidelity of the molecular models under study. AMBERff precision, coupled with NAMD’s parallel computing capabilities, makes simulations of large and more complex models possible.
Building of Synergy between AMBERff and NAMD
NAMD uses a combination of PSF/JS and CHARMM format parameter files to read AMBERff within the current implementation’s framework (i.e., under NAMD configuration: Amber off, ParaTypeCHARMM on). This means that the AMBERff parameters are assessed in the CHARMMff functional form.
The usage of symbols, spaces, and integers, together with case sensitivity, are essential components of AMBERff atom-type standards. On the other hand, NAMD rejects leading integers, ignores symbols and spaces, and reads atom types in CHARMM format as capitalized. In order to solve this, an atom-type prefix system is presented, which manages numbers in a straightforward way and encodes information lost while neglecting cases and symbols. Prefixes denote equivalent characters in the atom type they rename. They are composed of capital letters and contain the same number of characters as the original atom type. This guarantees that the newly-referred atom types are distinct and that NAMD interprets them correctly, making the import of AMBERff parameters easier.
Two distinct 1- 4 nonbonded scaling factors (SCNBs) are used by the most recent AMBERff for lipids, Lipid21, to reduce van der Waals interactions between atoms separated by three bonds. One SCNB was utilized in previous parameter sets, which might have changed for different force fields. The engine applies AMBER format files, which are written in PRMTOP, and allocates SCNB on a per-dihedral basis. On the other hand, force field files in the CHARMM format allocate SCNB according to the kind of atom, giving nonbonded entries prescaled Lennard-Jones parameters. New types are provided to identify atoms whose nonbonded scaling varies on the interaction partner to address mixed scaling scenarios. Lennard-Jones parameters for 1–4 pairings involving these atoms are corrected using CHARMM’s NBFix.
With the exception of histidine, the current implementation of the AMBERff atom and residue names has been maintained. The three-letter residue name convention for standard amino acids, established by the RCSB Protein Data Bank (PDB), is utilized by both AMBERff and CHARMMff. To indicate the presence of hydrogen at the ϵ, δ, or both ϵ and δ locations, histidine is labeled HIE, HID, or HIP. Residue names are also used for alternate, nonterminal protonation states. Patches to introduce nonstandard residue names based on changes to disulfide linkages, terminal capping residues, and associated default residues are included in the implementation. For the AMBER-DYES fluorophore force field, patches were provided for bonding all conceivable linker-dye combinations and addressing unusual circumstances in which conditional reordering of erroneous dihedral declarations is necessary to produce accurate potential energies.
In AMBER force fields, PRMTOP creation entails adding to or changing historical parameter sets. Original parameter sets are saved as DAT files, and adjustments are stored as FRCMOD files according to AMBER protocol. LEAPRC and other resource files load all necessary parts for PRMTOP assembly. PSF and JS files include topology information, whereas X-PLOR or CHARMM format files are used by NAMD to load parameter details at runtime. Original parameter settings and revisions are supplied as distinct files in order to maintain the AMBER convention.
The implementation of AMBERff in psfgen and NAMD entails loading appropriate TOP, RTF, and STR files for the requested force field(s). The system can be submerged in a solvent box for neutralization or salt concentration once segments are constructed and patches are applied. According to the CHARMMff method, STR files provide solvent and ion parameters together with molecule topology and parameter data.
Initial coordinates and a PSF or JS file in X-PLOR format are written and sent to NAMD, and the recently released NAMDRC file is sourced. Similar to AMBERff’s LEAPRC, the NAMDRC loads pertinent PRM and STR parameter data for a specified force field and configures the simulation to turn on ParaTypeCHARMM and turn off Amber. To determine the appropriate 1–4 electrostatic scaling factor for AMBERff proteins, lipids, and nucleic acids, the value of 1–4 scaling should be set to 1/1.2 = 0.833333. These examples contain extra setup information needed to maintain AMBERff integrity while utilizing NAMD.
Road Ahead
The researchers present a realm of multi-million atom simulation, laying a bunch of opportunities in the field of research and development. The application of AMBERff to biomolecular systems of increasing size and complexity will reveal new opportunities to advance classical force field development and expand the resolution of the computational microscope. The rise of exascale computing and data analysis powered by machine learning positions researchers to examine the atomistic dynamics of massive biomolecular assemblies, including intact viruses, small organelles, and minimal cells.
Conclusion
A variety of computational tools have been used in the development of AMBERff, a force field for MD simulation engines. Other methods like CHAMBER provide support for CHARMMff in AMBER engines by translating PSF files to PRMTOP and are accessible through AMBER’s ParmEd. Whereas MDWiZ translates GROMACS files into inputs that can be read by a variety of simulation engines, such as NAMD and LAMMPS, TopoGromacs converts CHARMMff parameter and topology files into formats that are compatible with GROMACS. To facilitate interoperability and repeatability across MD tools, CHARMM-GUI, a web-based platform for biomolecular system building and protocol development, generates both CHARMMff and AMBERff inputs. When atom counts exceed approximately 10 million, memory-optimized NAMD becomes necessary, and for atom counts greater than 30 million, it becomes appropriate. Altogether, AMBERff provides a new scope of research in the field of MD Simulation of large atom systems.
Article Source: Reference Paper
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Deotima is a consulting scientific content writing intern at CBIRT. Currently she's pursuing Master's in Bioinformatics at Maulana Abul Kalam Azad University of Technology. As an emerging scientific writer, she is eager to apply her expertise in making intricate scientific concepts comprehensible to individuals from diverse backgrounds. Deotima harbors a particular passion for Structural Bioinformatics and Molecular Dynamics.
