15 research outputs found
Reproducibility of Free Energy Calculations Across Different Molecular Simulation Software
<div>
<div>
<div>
<p>Alchemical free energy calculations are an increasingly important modern simulation
technique. Contemporary molecular simulation software such as AMBER, CHARMM,
GROMACS and SOMD include support for the method. Implementation details vary
among those codes but users expect reliability and reproducibility, i.e. for a given molec-
ular model and set of forcefield parameters, comparable free energy should be obtained within statistical bounds regardless of the code used. Relative alchemical free energy
(RAFE) simulation is increasingly used to support molecule discovery projects, yet the
reproducibility of the methodology has been less well tested than its absolute counter-
part. Here we present RAFE calculations of hydration free energies for a set of small
organic molecules and demonstrate that free energies can be reproduced to within about
0.2 kcal/mol with aforementioned codes. Achieving this level of reproducibility requires
considerable attention to detail and packageâspecific simulation protocols, and no uni-
versally applicable protocol emerges. The benchmarks and protocols reported here
should be useful for the community to validate new and future versions of software for
free energy calculations.</p></div></div></div
Evaluation of Selected Classical Force Fields for Alchemical Binding Free Energy Calculations of Protein-Carbohydrate Complexes
Proteinâcarbohydrate
recognition is crucial in many vital
biological processes including hostâpathogen recognition, cell-signaling,
and catalysis. Accordingly, computational prediction of proteinâcarbohydrate
binding free energies is of enormous interest for drug design. However,
the accuracy of current force fields (FFs) for predicting binding
free energies of proteinâcarbohydrate complexes is not well
understood owing to technical challenges such as the highly polar
nature of the complexes, anomerization, and conformational flexibility
of carbohydrates. The present study evaluated the performance of alchemical
predictions of binding free energies with the GAFF1.7/AM1-BCC and
GLYCAM06j force fields for modeling proteinâcarbohydrate complexes.
Mean unsigned errors of 1.1 ± 0.06 (GLYCAM06j) and 2.6 ±
0.08 (GAFF1.7/AM1-BCC) kcal·mol<sup>â1</sup> are achieved
for a large data set of monosaccharide ligands for <i>Ralstonia
solanacearum</i> lectin (RSL). The level of accuracy provided
by GLYCAM06j is sufficient to discriminate potent, moderate, and weak
binders, a goal that has been difficult to achieve through other scoring
approaches. Accordingly, the protocols presented here could find useful
applications in carbohydrate-based drug and vaccine developments
CXCR6, a Newly Defined Biomarker of Tissue-Specific Stem Cell Asymmetric Self-Renewal, Identifies More Aggressive Human Melanoma Cancer Stem Cells
Background: A fundamental problem in cancer research is identifying the cell
type that is capable of sustaining neoplastic growth and its origin from normal
tissue cells. Recent investigations of a variety of tumor types have shown that
phenotypically identifiable and isolable subfractions of cells possess the
tumor-forming ability. In the present paper, using two lineage-related human
melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative
line IGR37, two main observations are reported. The first one is the first
phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs)
from mutated tissue-specific stem cells; and the second one is the
identification of a more aggressive subpopulation of CSCs in melanoma that are
CXCR6+. Conclusions/Significance: The association of a more aggressive tumor
phenotype with asymmetric self-renewal phenotype reveals a previously
unrecognized aspect of tumor cell physiology. Namely, the retention of some
tissue-specific stem cell attributes, like the ability to asymmetrically
self-renew, impacts the natural history of human tumor development. Knowledge
of this new aspect of tumor development and progression may provide new targets
for cancer prevention and treatment
Longbow: A Lightweight Remote Job Submission Tool
We present Longbow, a lightweight console-based remote job submission tool and library. Longbow allows the user to quickly and simply run jobs on high performance computing facilities without leaving their familiar desktop environment. Not only does Longbow greatly simplify the management of compute- intensive jobs for experienced researchers, it also lowers the technical barriers surrounding high perfor-mance computation for the next generation of scientists and engineers. Longbow has already been used to remotely submit jobs in a number of projects and has the potential to redefine the manner in which high performance computers are used
Hydration Structure and Water Exchange Reaction of Nickel(II) Ion:Â Classical and QM/MM Simulations
Influence of Backbone Conformations of Human Carbonic Anhydrase II on Carbon Dioxide Hydration:Â Hydration Pathways and Binding of Bicarbonate
Reinvent 4: Modern AIâdriven generative molecule design
Abstract REINVENT 4 is a modern open-source generative AI framework for the design of small molecules. The software utilizes recurrent neural networks and transformer architectures to drive molecule generation. These generators are seamlessly embedded within the general machine learning optimization algorithms, transfer learning, reinforcement learning and curriculum learning. REINVENT 4 enables and facilitates de novo design, R-group replacement, library design, linker design, scaffold hopping and molecule optimization. This contribution gives an overview of the software and describes its design. Algorithms and their applications are discussed in detail. REINVENT 4 is a command line tool which reads a user configuration in either TOML or JSON format. The aim of this release is to provide reference implementations for some of the most common algorithms in AI based molecule generation. An additional goal with the release is to create a framework for education and future innovation in AI based molecular design. The software is available from https://github.com/MolecularAI/REINVENT4 and released under the permissive Apache 2.0 license. Scientific contribution. The software provides an openâsource reference implementation for generative molecular design where the software is also being used in production to support inâhouse drug discovery projects. The publication of the most common machine learning algorithms in one code and full documentation thereof will increase transparency of AI and foster innovation, collaboration and education
Reproducibility of Free Energy Calculations Across Different Molecular Simulation Software
Alchemical free energy calculations are an increasingly important modern simulation
technique. Contemporary molecular simulation software such as AMBER, CHARMM,
GROMACS and SOMD include support for the method. Implementation details vary
among those codes but users expect reliability and reproducibility, i.e. for a given molec-
ular model and set of forcefield parameters, comparable free energy should be obtained within statistical bounds regardless of the code used. Relative alchemical free energy
(RAFE) simulation is increasingly used to support molecule discovery projects, yet the
reproducibility of the methodology has been less well tested than its absolute counter-
part. Here we present RAFE calculations of hydration free energies for a set of small
organic molecules and demonstrate that free energies can be reproduced to within about
0.2 kcal/mol with aforementioned codes. Achieving this level of reproducibility requires
considerable attention to detail and packageâspecific simulation protocols, and no uni-
versally applicable protocol emerges. The benchmarks and protocols reported here
should be useful for the community to validate new and future versions of software for
free energy calculations.</div
Recommended from our members
Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the FreeSolv database.
Solvation free energies can now be calculated precisely from molecular simulations, providing a valuable test of the energy functions underlying these simulations. Here, we briefly review "alchemical" approaches for calculating the solvation free energies of small, neutral organic molecules from molecular simulations, and illustrate by applying them to calculate aqueous solvation free energies (hydration free energies). These approaches use a non-physical pathway to compute free energy differences from a simulation or set of simulations and appear to be a particularly robust and general-purpose approach for this task. We also present an update (version 0.5) to our FreeSolv database of experimental and calculated hydration free energies of neutral compounds and provide input files in formats for several simulation packages. This revision to FreeSolv provides calculated values generated with a single protocol and software version, rather than the heterogeneous protocols used in the prior version of the database. We also further update the database to provide calculated enthalpies and entropies of hydration and some experimental enthalpies and entropies, as well as electrostatic and nonpolar components of solvation free energies