An assessment of protein–ligand binding site polarizability

Abstract

Electronic polarizability, an important physical property of biomolecules, is currently ignored in most biomolecular calculations. Yet, it is widely believed that polarization could account for a substantial fraction of the total nonbonded energy of a system. This belief is supported by studies of small complexes in vacuum. This perception is driving the development of a new class of polarizable force fields for biomolecular calculations. However, the quantification of this term for protein-ligand complexes has never been attempted. Here we explore the polarizable nature of protein-ligand complexes in order to evaluate the importance of this effect. We introduce two indexes describing the polarizability of protein binding sites. These we apply to a large range of pharmaceutically relevant complexes. We offer a recommendation of particular complexes as test systems with which to determine the effects of polarizability and as test cases with which to test the new generation of force fields. Additionally, we provide a tabulation of the amino acid composition of these binding sites and show that composition can be specific for certain classes of proteins. We also show that the relative abundance of some amino acids is different in binding sites than elsewhere in a protein's structure.

Morphological transition difference of linear and cyclic block copolymer with polymer blending in a selective solvent by combining dissipative particle dynamics and all-atom molecular dynamics simulations based on the ABEEM polarizable force field

“…The results obtained indicate that ABEEM polarizable force eld presents a good description of the nonbonded interaction in the system not at the cost of sacricing the transferability of parameters, which oen occurs in nonpolarizable force elds. 28 In this way, the combination of DPD and molecular dynamics based on a polarizable force eld provides a desirable way to bridge the gap between atomistic and mesoscopic simulation. The key interaction parameters in DPD simulation can be obtained from all-atom molecular dynamics simulation.…”

Structure and Mechanism of Action of Tau Aggregation Inhibitors

“…The resulting structures are planar and highly “polarizable”, meaning that electron density can easily shift about the molecule when exposed to an external electric field, such as an adjacent dipole or ion. These properties are ideal for supporting van der Waals interactions with protein binding partners containing their own highly polarizable moieties, such as aromatic side chains [112, 113]. The resulting interactions are nearly electrostatic in strength [114].…”

Quantum Mechanics/Molecular Mechanics Strategies for Docking Pose Refinement: Distinguishing between Binders and Decoys in CytochromecPeroxidase

“…Other studies have verified that QM/MM is useful in predicting the binding free energy. [43][44][45] While QM/MM approaches may provide a good description of the energetics of a static system, it is generally too expensive to do any sort of dynamics study.…”

“…An improvement is also shown in the root mean square deviation (RMSD) of the redocked poses with respect to the crystallographically resolved ligands. Other studies have verified that QM/MM is useful in predicting the binding free energy. − While QM/MM approaches may provide a good description of the energetics of a static system, it is generally too expensive to do any sort of dynamics study.…”