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Optimal Bond Constraint Topology for Molecular Dynamics Simulations of Cholesterol.

ABSTRACT: We recently observed artificial temperature gradients in molecular dynamics (MD) simulations of phase-separating ternary lipid mixtures using the Martini 2 force field. We traced this artifact to insufficiently converged bond length constraints with typical time steps and default settings for the linear constraint solver (LINCS). Here, we systematically optimize the constraint scaffold of cholesterol. With massive virtual sites in an equimomental arrangement, we accelerate bond constraint convergence while preserving the original cholesterol force field and dynamics. The optimized model does not induce nonphysical temperature gradients even at relaxed LINCS settings and is at least as fast as the original model at the strict LINCS settings required for proper thermal sampling. We provide a python script to diagnose possible problems with constraint convergence for other molecules and force fields. Equimomental constraint topology optimization can also be used to boost constraint convergence in atomistic MD simulations of molecular systems.

SUBMITTER: Fabian B

PROVIDER: S-EPMC10018735 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Optimal Bond Constraint Topology for Molecular Dynamics Simulations of Cholesterol.

Fábián Balázs B Thallmair Sebastian S Hummer Gerhard G

Journal of chemical theory and computation 20230217 5

We recently observed artificial temperature gradients in molecular dynamics (MD) simulations of phase-separating ternary lipid mixtures using the Martini 2 force field. We traced this artifact to insufficiently converged bond length constraints with typical time steps and default settings for the linear constraint solver (LINCS). Here, we systematically optimize the constraint scaffold of cholesterol. With massive virtual sites in an equimomental arrangement, we accelerate bond constraint conver ...[more]

PMID: 36800179

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Project description:The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol-binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N-terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C-terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150-X-Y152-X(3)-R156 and R135-X(2)-Y138-X(2)-L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC-resembling motif that we observed in TM I (residues L17-X(2)-F20-X(3)-R24) and to CRAC in TM V. We expect that the CRAC-like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.

Dataset Information

Optimal Bond Constraint Topology for Molecular Dynamics Simulations of Cholesterol.

Publications

Optimal Bond Constraint Topology for Molecular Dynamics Simulations of Cholesterol.

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