Higher Accuracy Achieved in the Simulations of Protein Structure Refinement, Protein Folding, and Intrinsically Disordered Proteins Using Polarizable Force Fields

Abstract

The accuracy of molecular mechanics force fields is of vital importance in biomolecular simulations. However, the admittedly more accurate polarizable force fields were recently reported to be less able to reproduce the experimental properties in comparison to additive force fields in some cases. Here, we perform long-time-scale molecular dynamics simulations to systematically evaluate the effect of explicit electronic polarization in polarizable force fields. The results show that the inclusion of electrostatic polarization effect in polarizable force fields can improve their accuracies in protein structure refinement and generate conformational ensembles more approximate to experiments for intrinsically disordered proteins. In contrast, it is difficult for polarizable force fields to approach the native structure, let alone to predict the native state when it is unknown a priori in the real protein structure predictions. We speculate that these effects might be attributed to the preference of protein–water interactions in polarizable force fields.

Out of the Dark and Into the Light: A New View of Phytochrome Photobodies

“…Conversely, as warm temperatures lead to the thermal reversion of Pfr back to Pr and the dissipation of photobodies, temperature may also regulate the phase separation of photobodies in vivo ( Figure 3 ). Models that have been used to describe biomolecular condensate formation are the “stickers and spacers” model and the “scaffold and client” model ( Semenov and Rubinstein, 1998 ; Banani et al, 2017 ; Posey et al, 2018 ; Wang A. et al, 2018 ; Holehouse, 2019 ). In the former model, stickers are portions of an amino acid sequence that promote intermolecular interactions, while the spacers are regions that are inert in promoting interactions ( Wang A. et al, 2018 ).…”

“…Models that have been used to describe biomolecular condensate formation are the “stickers and spacers” model and the “scaffold and client” model ( Semenov and Rubinstein, 1998 ; Banani et al, 2017 ; Posey et al, 2018 ; Wang A. et al, 2018 ; Holehouse, 2019 ). In the former model, stickers are portions of an amino acid sequence that promote intermolecular interactions, while the spacers are regions that are inert in promoting interactions ( Wang A. et al, 2018 ). In the later model, scaffold proteins are necessary for condensate formation to occur, whereas client proteins localize to the condensate but are not necessary or sufficient for formation ( Banani et al, 2017 ).…”

Advances in enhanced sampling molecular dynamics simulations for biomolecules

“…On the other hand, the precision of force fields is another critical factor that affects DOI:10.1063/1674-0068/cjcp1905091 c ⃝2019 Chinese Physical Society the accuracy of MD simulations. The most significant advantage of enhanced sampling can only be achieved when these methods are in conjunction with highprecision force fields [156]. As reported by Shaw and co-workers, none of the state-of-the-art force fields can simultaneously provide accurate descriptions for both folded and disordered proteins [157].…”

Advances in Molecular Dynamics Simulations and Enhanced Sampling Methods for the Study of Protein Systems

“…Recent improvements in the aforementioned polarizable force fields include the incorporation of screening effects and charge penetration corrections to precisely model the electrostatic energy of short-range interactions, and the consideration of anisotropic polarization of water/solvent molecules to further justify the thesis of polarizability being a many-body effect [ 127 , 132 , 138 , 139 , 140 ]. Consideration of the electrostatic polarization effect has positive implications on numerous protein-related studies [ 141 , 142 , 143 , 144 ]. The use of AMOEBA polarizable force field to reproduce the free energy profiles of the permeation of K + and Na + ions through the Gramicidin A channel showed good agreement with experimental observations, in comparison to classical MD simulations [ 145 ].…”