Predicting fragment binding modes using customized Lennard-Jones potentials in short molecular dynamics simulations

2024/12/23 by Christopher Vorreiter, Dina Robaa, Wolfgang Sippl · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Chemistry · #Protein Structure and Dynamics #Mass Spectrometry Techniques and Applications #Crystallography and molecular interactions

paper · doi:10.1016/j.csbj.2024.12.017

openalex publication_date 2024/12/23 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/25

Abstract

Reliable in silico prediction of fragment binding modes remains a challenge in current drug design research. Due to their small size and generally low binding affinity, fragments can potentially interact with their target proteins in different ways. In the current study, we propose a workflow aimed at predicting favorable fragment binding sites and binding poses through multiple short molecular dynamics simulations. Tailored Lennard-Jones potentials enable the simulation of systems with high concentrations of identical fragment molecules surrounding their respective target proteins. In the present study, descriptors and binding free energy calculations were implemented to filter out the desired fragment position. The proposed method was tested for its performance using four epigenetic target proteins and their respective fragment binders and showed high accuracy in identifying the binding sites as well as predicting the native binding modes. The approach presented here represents an alternative method for the prediction of fragment binding modes and may be useful in fragment-based drug discovery when the corresponding experimental structural data are limited. • Lennard-Jones potentials enabled the simulation of high-concentrated fragments. • Fragments were simulated in the presence of their unbound target proteins. • Pocket descriptors were implemented for identifying the fragment binding sites. • Candidates for binding mode reproduction were identified by fragment mobilities. • QM/MM-GBSA interaction energies indicated native-like fragment binding modes.

Citations

• Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Models
• Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution
• Development and testing of a general amber force field
• Parameterization of Monovalent Ions for the OPC3, OPC, TIP3P-FB, and TIP4P-FB Water Models
• Cohesion

Cited by

• Energy-driven innovations in computational de novo protein engineering

Discussions

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