Host Dynamics under General-Purpose Force Fields

Abstract

Macrocyclic hosts as prototypical receptors to gaseous and drug-like guests are crucial components in pharmaceutical research. The external guests are often coordinated at the center of these macromolecular containers. The formation of host–guest coordination is accompanied by the broken of host–water and host–ion interactions and sometimes also involves some conformational rearrangements of the host. A balanced description of various components of interacting terms is indispensable. However, up to now, the modeling community still lacks a general yet detailed understanding of commonly employed general-purpose force fields and the host dynamics produced by these popular selections. To fill this critical gap, in this paper, we profile the energetics and dynamics of four types of popular macrocycles, including cucurbiturils, pillararenes, cyclodextrins, and octa acids. The presented investigations of force field definitions, refitting, and evaluations are unprecedently detailed. Based on the valuable observations and insightful explanations, we finally summarize some general guidelines on force field parametrization and selection in host–guest modeling.

Screening Power of End-Point Free-Energy Calculations in Cucurbituril Host–Guest Systems

“…The chemical structures of all molecules are either grabbed from the PubChem database or constructed by modifications of existing molecules of similar chemical structures (i.e., template modeling). According to our previous validation of popular charge schemes, the restrained electrostatic potential (RESP) 41 scheme serves as a robust and accurate option for many macrocyclic hosts including cucurbiturils 22,23,30 and many other organic and inorganic molecules. 42−45 We thus optimize each molecule B3LYP 46−48 /6-31G* and then derive RESP charges based on the HF 49−51 /6-31G* electrostatic potential.…”

“…The other parameters of fixed-charge force fields (e.g., bond stretching, torsion, and vdW) are grabbed from the transferable GAFF2 29 parameter set for all guest molecules, while for the macrocyclic hosts, we apply either GAFF or GAFF2 in our modeling due to the observed differences in host dynamics reported in our recent works. 21,30 Two end-point sampling protocols are considered in the current work. The first one is the popular single-trajectory formalism that samples only the host−guest complex, while the other is the three-trajectory protocol that samples both the bound and unbound states and thus takes the binding-induced conformational change into consideration.…”

“…The chemical structures of all molecules are either grabbed from the PubChem database or constructed by modifications of existing molecules of similar chemical structures (i.e., template modeling). According to our previous validation of popular charge schemes, the restrained electrostatic potential (RESP) scheme serves as a robust and accurate option for many macrocyclic hosts including cucurbiturils ,, and many other organic and inorganic molecules. − We thus optimize each molecule B3LYP − /6-31G* and then derive RESP charges based on the HF − /6-31G* electrostatic potential. The other parameters of fixed-charge force fields (e.g., bond stretching, torsion, and vdW) are grabbed from the transferable GAFF2 parameter set for all guest molecules, while for the macrocyclic hosts, we apply either GAFF or GAFF2 in our modeling due to the observed differences in host dynamics reported in our recent works. , …”

“…Similarly, for torsional interactions, more molecules (around 400) have been added to the data set, generating more ab initio data as the training reference. For the specific host family of cucurbiturils, our recent investigation on host dynamics identifies noticeable differences between dynamic behaviors produced by general-purpose force fields . The by-term force-field comparison suggests the variations of two torsional potentials to be the reasons, although many other terms (e.g., bond-stretching, angle-bending, and vdW terms) also exhibit alterations of varying degrees.…”

“…For the specific host family of cucurbiturils, our recent investigation on host dynamics identifies noticeable differences between dynamic behaviors produced by general-purpose force fields. 30 The by-term force-field comparison suggests the variations of two torsional potentials to be the reasons, although many other terms (e.g., bond-stretching, angle-bending, and vdW terms) also exhibit alterations of varying degrees. The complexity of the force-field dependence generally becomes higher with increased ring size.…”