Further along the Road Less Traveled: AMBER ff15ipq, an Original Protein Force Field Built on a Self-Consistent Physical Model

Abstract

We present the AMBER ff15ipq force field for proteins, the second-generation force field developed using the Implicitly Polarized Q (IPolQ) scheme for deriving implicitly polarized atomic charges in the presence of explicit solvent. The ff15ipq force field is a complete rederivation including more than 300 unique atomic charges, 900 unique torsion terms, 60 new angle parameters, and new atomic radii for polar hydrogens. The atomic charges were derived in the context of the SPC/Eb water model, which yields more-accurate rotational diffusion of proteins and enables direct calculation of nuclear magnetic resonance (NMR) relaxation parameters from molecular dynamics simulations. The atomic radii improve the accuracy of modeling salt bridge interactions relative to contemporary fixed-charge force fields, rectifying a limitation of ff14ipq that resulted from its use of pair-specific Lennard-Jones radii. In addition, ff15ipq reproduces penta-alanine J-coupling constants exceptionally well, gives reasonable agreement with NMR relaxation rates, and maintains the expected conformational propensities of structured proteins/peptides, as well as disordered peptides—all on the microsecond (μs) time scale, which is a critical regime for drug design applications. These encouraging results demonstrate the power and robustness of our automated methods for deriving new force fields. All parameters described here and the mdgx program used to fit them are included in the AmberTools16 distribution.

Evaluating amber force fields using computed NMR chemical shifts

“…MD simulations using 6 different AMBER force fields were carried out on each of these proteins using GPU accelerated AMBER version 16 and the ff94, ff96, ff99SB, ff14SB, ff14ipq and ff15ipq force fields. 20,22,31,34,37,38 All protein structures were solvated to form an octahedral TIP3P water box that extended 12 Å beyond the protein.…”

“…Performance with respect to α‐helical and β‐sheet oligopeptides was significantly improved over ff99SB. In 2016, ff15ipq, a second generation force field based on the IpolQ charge model was released . This force field included a new derivation of more than 300 atomic charges, 900 torsions terms and 60 new angle parameters along with new atomic radii for polar hydrogens.…”

“…In 2016, ff15ipq, a second generation force field based on the IpolQ charge model was released. 38 This force field included a new derivation of more than 300 atomic charges, 900 torsions terms and 60 new angle parameters along with new atomic radii for polar hydrogens. In the present study, a series of 30 MD simulations are carried out on 8 model proteins for each of these AMBER force fields.…”

“…This is expected because ff94 represents the state of the art two decades ago. The regions with the smallest improvements are associated with the presence of helical secondary structure(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(56)(57)(58)(59). The pattern fractions for this example are presented in…”

MDMS: Software Facilitating Performing Molecular Dynamics Simulations

“…S21). Currently supported protein force fields are ff14sb, ff15ipq, fb15, ff03, and ff03ua . For water models, the user can choose between tip3p, tip4pew, and spce .…”