Benchmarking polarizable and non-polarizable force fields for Ca2+–peptides against a comprehensive QM dataset

Abstract

Explicit description of atomic polarizability is critical for the accurate treatment of inter-molecular interactions by force fields (FFs) in molecular dynamics (MD) simulations aiming to investigate complex electrostatic environments such as metal-binding sites of metalloproteins. Several models exist to describe key monovalent and divalent cations interacting with proteins. Many of these models have been developed from ion-amino-acid interactions and/or aqueous-phase data on cation solvation. The transferability of these models to cation-protein interactions remains uncertain. Herein, we assess the accuracy of existing FFs by their abilities to reproduce hierarchies of thousands of Ca 2+ -dipeptide interaction energies based on density-functional theory calculations. We find that the Drude polarizable FF, prior to any parameterization, better approximates the QM interaction energies than any of the non-polarizable FFs. Nevertheless, it required improvement in order to address polarization catastrophes where, at short Ca 2+ -carboxylate distances, the Drude particle of oxygen overlaps with the divalent cation. To ameliorate this, we identified those conformational properties that produced the poorest prediction of interaction energies to reduce the parameter space for optimization. We then optimized the selected cation-peptide parameters using Boltzmann-weighted fitting and evaluated the resulting parameters in MD simulations of the N-lobe of calmodulin. We also parameterized and evaluated the CTPOL FF, which incorporates charge-transfer and polarization effects in additive FFs. This work shows how QM-driven parameter development, followed by testing in condensed-phase simulations, may yield FFs that can accurately capture the structure and dynamics of ion-protein interactions.

Better force fields start with better data: A data set of cation dipeptide interactions

“…The failures of established biomolecular force fields when describing cation-peptide systems may result from a central underlying assumption – modeling atoms by fixed point charges and neglecting charge transfer and polarization effects, while both are crucial to ionic systems 20 – 23 . Introducing more physics to the model appears a promising route to improve force fields: The inclusion of electronic polarization and charge transfer plays a central role in the next generations of biomolecular force fields 24 – 26 . However, including additional terms leads to force fields with way more parameters, which makes parameterization more challenging 27 , 28 , in particular in the absence of high-resolution experimental data of less stable conformations, i.e.…”

“…Instead, DFT-PBE+vdW calculations also included high-energy conformers. The data we provide is particularly focused on parameterizing non-bonded interactions: The above-mentioned cation-peptide interaction energies were already used to tune force fields parameters of non-bonded interactions 26 , 82 . The comparison to DFT-based vdW energies computed with the Tkatchenko-Scheffler formalism 58 is useful to evaluate or adjust the non-bonded Lennard-Jones parameters ε and σ .…”

“…The potential usage of our data set has been confirmed in ref. 26 . In this work, our data set was used to assess the accuracy of existing FFs by their abilities to reproduce quantum mechanical (QM) interaction energies of Ca 2+ -dipeptide.…”

Better force fields start with better data -- A data set of cation dipeptide interactions

“…The data we provide is particularly focused on parameterizing non-bonded interactions: The above mentioned cation-peptide interaction energies were already used to tune force fields parameters of non-bonded interactions. 24,81 The comparison to DFT-based vdW energies computed with the Tkatchenko-Scheffler formalism 57 is useful to evaluate or adjust the non-bonded Lennard-Jones parameters ε and σ . Importantly, due to the spread over high and low energy conformations, diverse substructures and environments (due to cation binding), a range of partial charge values is sampled that informs about polarization and charge transfer.…”

“…The potential usage of our data set has been confirmed in reference. 24 In this work, our data set was used to assess the accuracy of existing FFs by their abilities to reproduce quantum mechanical (QM) interaction energies of Ca 2+ -dipeptide. By relating the parameter space to conformational space, the utility of our data set as a reference for future optimization of polarizable force fields is illustrated.…”