CUFIX: Non-bonded Fix (NBFIX) parameters for the CHARMM and AMBER force fields

Over the past decades, molecular dynamics (MD) simulations of biomolecules have become a mainstream biophysics technique. As the length and time scales amenable to the MD method increase, shortcomings of the empirical force fields—which were developed and validated using relatively short simulations of small molecules—become apparent. One common artifact is artificial aggregation of water-soluble biomolecules, which has been observed in a variety of systems, including electrolyte solutions, intrinsically disordered proteins, lipid bilayer membranes and DNA arrays. Here, we report a systematic refinement of Lennard-Jones parameters (CUFIX) describing amine-carboxyate, amine-phosphate, and aliphatic carbon-carbon interactions, which brings the results of MD simulations of proteins, nucleic acids, and lipids in remarkable agreement with experiments. To refine the amine-carboxylate and aliphatic carbon-carbon interactions, we matched the simulated osmotic pressure of amino acid solutions to the experimental data. Similarly, we refined the amine-phosphate interaction by matching the simulated and experimental osmotic pressure of a DNA array. We demonstrate the utility of our CUFIX corrections through simulations of lysine-mediated DNA—DNA forces, lipid-bilayer membranes and folded proteins. As our refinement neither affects the existing parameterization of bonded interaction nor does it alter the solvation free energies, it improves realism of an MD simulation without introducing any new artifacts.

How to use CUFIX:

  • AMBER ff99 variants in the Gromacs format:
    • > Option 1: If you want to use a complete package that was used for our publications, download ff99sb-ildn-phi-bsc0-cufix. Make sure our CUFIX corrections are optimized with the TIP3P water model (use tip3p.itp).
    • > Option 2: If you want to integrate CUFIX to your version of AMBER ff99 variants, follow these steps.
      • >> Download ff99sb-ildn-phi-bsc0-cufix package.
      • >> Copy the following files in the downloaded package to your gromacs-format ff99 folder: cufix.itp, mg-sol6.itp mg-sol6.pdb ca-sol7.itp ca-sol7.pdb.
      • >> Replace atom types of O1P and O2P atoms (O2) with ON2 for all nucleotides in dna.rtp and rna.rtp. ON2 atom type is defined in cufix.itp.
      • >> Add #include "cufix.itp" to forcefield.itp between #include "ffnonbonded.itp" and #include "ffbonded.it".
      • >> Delete the following ions from ffnonbonded.itp: Li, Na, K, Cl, MG, Rb, Cs, F, Br, I. CUFIX uses new ion parameters by the Cheatham group.
      • >> You're ready to go! Make sure that CUFIX is optimized with tip3p.itp.
  • ​AMBER ff99 variants in AMBER format
    • > Download frcmod.ff99cufix.
    • > This frcmod file will work with any ff99 variant protein force field in combination with leaprc.water.tip3p. frcmod files for nucleic acids and lipid are coming soon.
    • For example, do the followings in the leap command:
      • source <A FF99 PROTEIN FORCE FIELD CMD FILE>
        source leaprc.water.tip3p
        cufix = loadamberparams frcmod.ff99cufix
  • CHARMM 36/27/22 force fields
    • > Download CHARMM36/27/22 force fields: stream file for CHARMM and NAMD packages
    • > Replace the standard toppar_water_ions.str with the downloaded file.
    • > Our CUFIX corrections are optimized for CHARMM36-version ion parameters (LIT, SOD, K, MG, CAL and CL) with CHARMM-format TIP3P water model.
    • > For magnesium and calcium ions, we use hexa- or hepta-hydrated forms, respectively. The downloaded file contains RESI definitions for these Mg/Ca-water complexes, but additional bonds (extrabonds) are required between Mg/Ca and water oxygen atoms. Please refer to our DNA origami tutorial to learn how to use it.
  • Anton

 

Jejoong Yoo, and Aleksei Aksimentiev Journal of Physical Chemistry Letters (2016)

Recent advances in computational technology have enabled brute-force molecular dynamics (MD) simulations of protein folding using physics-based molecular force fields. The extensive sampling of protein conformations afforded by such simulations revealed, however, considerable compaction of the protein conformations in the unfolded state, which is inconsistent with experiment. Here, we show that a set of surgical corrections to nonbonded interactions between amine nitrogen–carboxylate oxygen and aliphatic carbon–carbon atom pairs can considerably improve the realism of protein folding simulations. Specifically, we show that employing our corrections in ∼500 μs all-atom replica-exchange MD simulations of the WW domain and villin head piece proteins increases the size of the denatured proteins’ conformations and does not destabilize the native conformations of the proteins. In addition to making the folded conformations a global minimum of the respective free energy landscapes at room temperature, our corrections also make the free energy landscape smoother, considerably accelerating the folding kinetics and, hence, reducing the computational expense of a protein folding simulation.

Jejoong Yoo, and Aleksei Aksimentiev Journal of Chemical Theory and Computation (2016)

Over the past decades, molecular dynamics (MD) simulations of biomolecules have become a mainstream biophysics technique. As the length and time scales amenable to the MD method increase, shortcomings of the empirical force fields, which have been developed and validated using relatively short simulations of small molecules, become apparent. One common artifact is aggregation of water-soluble biomolecules driven by artificially strong charge–charge interactions. Here, we report a systematic atom pair-specific refinement of Lennard-Jones parameters (NBFIX) describing amine–carboxylate and amine–phosphate interactions, which bring MD simulations of basic peptide-mediated nucleic acid assemblies and lipid bilayer membranes into better agreement with experimental data. As our refinement does not affect the existing parametrization of bonded interactions or alter the solvation free energies, it improves the realism of an MD simulation without introducing additional artifacts.

Jejoong Yoo, James Wilson, and Aleksei Aksimentiev Biopolymers (2016)

Calcium ions (Ca2+) play key roles in various fundamental biological processes such as cell signaling and brain function . Molecular dynamics (MD) simulations have been used to study such interactions, however, the accuracy of the Ca2+ models provided by the standard M D force fields has not been rigorously tested. Here, we assess the performance of the Ca2+ models from the most popular classical force fields AMBER and CHARMM by computing the osmotic pressure of model compounds and the free energy of DNA–DNA inter act i on s. In the simulations performed using the two standard models, Ca2+ ions are seen to form artificial clusters with chloride, acetate, and phosphate species; the osmotic pressure of CaAc2and CaCl2solutions is a small fraction of the experimental values for both force fields. Using the standard parameterization of Ca2+ ions in the simulations of Ca2+-mediated DNA-DNA interact ions leads to qualitatively wrong outcomes: both AMBER and CHARMM simulations suggest strong inter-DNA attraction whereas, in experiment, DNA molecules repel one another. The artificial attraction of Ca2+to DNA phosphate is strong enough to affect the direction of the electric field-driven translocation of DNA through a solid-state nanopore. To address these shortcomings of the standard Ca2+ model, we introduce a custom model of a hydrated Ca2+ ion and show that using our model brings the results of the above MD simulations in quantitative agreement with experiment. Our improved model of Ca2+ can be readily applied to MD simulations of various biomolecular systems, including nucleic acids, proteins and lipid bilayer membranes.

Jejoong Yoo, and Aleksei Aksimentiev The Journal of Physical Chemistry Letters (2012)

Atomic-scale modeling of compacted nucleic acids has the ability to reveal the inner workings of spectacular biomolecular machines, yet the outcome of such modeling efforts sensitively depends on the accuracy of the underlying computational models. Our molecular dynamics simulations of an array of 64 parallel duplex DNA revealed considerable artifacts of cation−DNA phosphate interactions in CHARMM and AMBER parameter sets: both the DNA arrangement and the pressure inside the DNA arrays were found to be in considerable disagreement with experiment. To improve the models, we fine-tuned van der Waals interaction parameters for specific ion pairs to reproduce experimental osmotic pressure of binary electrolyte solutions of biologically relevant ions. Repeating the DNA array simulations using our parameters produced results consistent with experiment. Our improved parametrization can be directly applied to molecular dynamics simulations of various charged biomolecular systems, including nucleic acids, proteins, and lipid bilayer membranes.

Jejoong Yoo, Hajin Kim, Aleksei Aksimentiev, and Taekjip Ha Nature Communications (2016)

Although proteins mediate highly ordered DNA organization in vivo, theoretical studies suggest that homologous DNA duplexes can preferentially associate with one another even in the absence of proteins. Here we combine molecular dynamics simulations with single-molecule fluorescence resonance energy transfer experiments to examine the interactions between duplex DNA in the presence of spermine, a biological polycation. We find that AT-rich DNA duplexes associate more strongly than GC-rich duplexes, regardless of the sequence homology. Methyl groups of thymine acts as a steric block, relocating spermine from major grooves to interhelical regions, thereby increasing DNA–DNA attraction. Indeed, methylation of cytosines makes attraction between GC-rich DNA as strong as that between AT-rich DNA. Recent genome-wide chromosome organization studies showed that remote contact frequencies are higher for AT-rich and methylated DNA, suggesting that direct DNA–DNA interactions that we report here may play a role in the chromosome organization and gene regulation.

Jejoong Yoo, and Aleksei Aksimentiev Nucleic Acids Research (2016)

Spontaneous assembly of DNA molecules into compact structures is ubiquitous in biological systems. Experiment has shown that polycations can turn electrostatic self-repulsion of DNA into attraction, yet the physical mechanism of DNA condensation has remained elusive. Here, we report the results of atomistic molecular dynamics simulations that elucidated the microscopic structure of dense DNA assemblies and the physics of interactions that makes such assemblies possible. Reproducing the setup of the DNA condensation experiments, we measured the internal pressure of DNA arrays as a function of the DNA–DNA distance, showing a quantitative agreement between the results of our simulations and the experimental data. Analysis of the MD trajectories determined the DNA–DNA force in a DNA condensate to be pairwise, the DNA condensation to be driven by electrostatics of polycations and not hydration, and the concentration of bridging cations, not adsorbed cations, to determine the magnitude and the sign of the DNA–DNA force. Finally, our simulations quantitatively characterized the orientational correlations of DNA in DNA arrays as well as diffusive motion of DNA and cations.

Jejoong Yoo, and Aleksei Aksimentiev J Phys Chem B (2012)

The concept of "ion atmosphere" is prevalent in both theoretical and experimental studies of nucleic acid systems, yet the spatial arrangement and the composition of ions in the ion atmosphere remain elusive, in particular when several ionic species (e.g., Na(+), K(+), and Mg(2+)) compete to neutralize the charge of a nucleic acid polyanion. Complementing the experimental study of Bai and co-workers (J. Am. Chem. Soc.2007, 129, 14981), here we characterize ion atmosphere around double-stranded DNA through all-atom molecular dynamics simulations. We demonstrate that our improved parametrization of the all-atom model can quantitatively reproduce the experimental ion-count data. Our simulations determine the size of the ion atmosphere, the concentration profiles of ionic species competing to neutralize the DNA charge, and the sites of the cations' preferential binding at the surface of double-stranded DNA. We find that the effective size of the ion atmosphere depends on both the bulk concentration and valence of ions: increasing either reduces the size of the atmosphere. Near DNA, the concentration of Mg(2+) is strongly enhanced compared to monovalent cations. Within the DNA grooves, the relative concentrations of cations depend on their bulk values. Nevertheless, the total charge of competing cations buried in the DNA grooves is constant and compensates for about ~30% of the total DNA charge.

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