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Tora3D: an autoregressive torsion angle prediction model for molecular 3D conformation generation.

ABSTRACT: Three-dimensional (3D) conformations of a small molecule profoundly affect its binding to the target of interest, the resulting biological effects, and its disposition in living organisms, but it is challenging to accurately characterize the conformational ensemble experimentally. Here, we proposed an autoregressive torsion angle prediction model Tora3D for molecular 3D conformer generation. Rather than directly predicting the conformations in an end-to-end way, Tora3D predicts a set of torsion angles of rotatable bonds by an interpretable autoregressive method and reconstructs the 3D conformations from them, which keeps structural validity during reconstruction. Another advancement of our method over other conformational generation methods is the ability to use energy to guide the conformation generation. In addition, we propose a new message-passing mechanism that applies the Transformer to the graph to solve the difficulty of remote message passing. Tora3D shows superior performance to prior computational models in the trade-off between accuracy and efficiency, and ensures conformational validity, accuracy, and diversity in an interpretable way. Overall, Tora3D can be used for the quick generation of diverse molecular conformations and 3D-based molecular representation, contributing to a wide range of downstream drug design tasks.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC10245430 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Tora3D: an autoregressive torsion angle prediction model for molecular 3D conformation generation.

Zhang Zimei Z Wang Gang G Li Rui R Ni Lin L Zhang RunZe R Cheng Kaiyang K Ren Qun Q Kong Xiangtai X Ni Shengkun S Tong Xiaochu X Luo Li L Wang Dingyan D Lu Xiaojie X Zheng Mingyue M Li Xutong X

Journal of cheminformatics 20230607 1

Three-dimensional (3D) conformations of a small molecule profoundly affect its binding to the target of interest, the resulting biological effects, and its disposition in living organisms, but it is challenging to accurately characterize the conformational ensemble experimentally. Here, we proposed an autoregressive torsion angle prediction model Tora3D for molecular 3D conformer generation. Rather than directly predicting the conformations in an end-to-end way, Tora3D predicts a set of torsion ...[more]

PMID: 37287071

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Project description:This groundbreaking study derives and tests several new dihedral torsion model potentials for constructing classical forcefields for atomistic simulations of materials. (1) The new angle-damped dihedral torsion (ADDT) model potential is preferred when neither contained equilibrium bond angle is linear (i.e., (θ eq ABC and θ eq BCD) ≠ 180°), at least one of the contained equilibrium bond angles is ≥ 130° (i.e., (θ eq ABC or θ eq BCD) ≥ 130°), and the dihedral torsion potential contains some odd-function contributions (i.e., U[ϕ] ≠ U[-ϕ]). (2) The new angle-damped cosine only (ADCO) model potential is preferred when neither contained equilibrium bond angle is linear (i.e., (θ eq ABC and θ eq BCD) ≠180°), at least one of the contained equilibrium bond angles is ≥ 130° (i.e., (θ eq ABC or θ eq BCD) ≥ 130°), and the dihedral torsion potential contains no odd-function contributions (i.e., U[ϕ] = U[-ϕ]). (3) The new constant amplitude dihedral torsion (CADT) model potential is preferred when neither contained equilibrium bond angle is linear (i.e., (θ eq ABC and θ eq BCD) ≠ 180°), both contained equilibrium bond angles are <130° (i.e., (θ eq ABC and θ eq BCD) < 130°), and the dihedral torsion potential contains some odd-function contributions (i.e., U[ϕ] ≠ U[-ϕ]). (4) The constant amplitude cosine only (CACO) model potential is preferred when neither contained equilibrium bond angle is linear (i.e., (θ eq ABC and θ eq BCD) ≠180°), both contained equilibrium bond angles are <130° (i.e., (θ eq ABC and θ eq BCD) <130°), and the dihedral torsion potential contains no odd-function contributions (i.e., U[ϕ] = U[-ϕ]). (5) The new angle-damped linear dihedral (ADLD) model potential is preferred when at least one contained equilibrium bond angle is linear (i.e., (θ eq ABC or θ eq BCD) = 180°). Most importantly, this article derives combined angle-dihedral coordinate branch equivalency conditions and angle-damping factors that ensure the angle-damped torsion model potentials (e.g., ADDT, ADCO, and ADLD) are mathematically consistent and continuously differentiable even as at least one contained bond angle approaches linearity (i.e., as (θ ABC or θ BCD) → 180°). This article introduces the torsion offset potential (TOP). I show the TOP gives rise in some materials to the unusual physical phenomenon of slip torsion. For various molecules, extensive quantitative comparisons to high-level quantum chemistry calculations (e.g., CCSD) and experimental vibrational frequencies showed these new dihedral torsion model potentials perform superbly.

Dataset Information

Tora3D: an autoregressive torsion angle prediction model for molecular 3D conformation generation.

Publications

Tora3D: an autoregressive torsion angle prediction model for molecular 3D conformation generation.

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