Quantum Mechanics and Molecular Mechanics in Biomolecular Systems

Hybrid quantum mechanics/molecular mechanics (QM/MM) approaches have transformed our ability to model complex biomolecular assemblies by combining rigorous electronic-structure methods for a chemically active region with efficient classical force fields for the surrounding environment. Advances in polarizable embedding and fluctuating-charge models enable mutual polarisation between the quantum and classical subsystems, improving the description of non-covalent interactions, solvent effects and response properties. State-of-the-art implementations now exploit graphical processing units and new reaction-field Hamiltonians to deliver analytical gradients, nonadiabatic couplings and optimised conical intersections in solution. These multiscale strategies support accurate predictions of solvatochromic shifts, spectroscopy and photochemistry in proteins, nucleic acids and drug–receptor complexes. By striking a balance between computational cost and chemical accuracy, QM/MM methods continue to deepen our mechanistic understanding of enzymatic catalysis, photobiological signalling and drug binding, guiding rational design in biotechnology and pharmacology.

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Quantum Mechanics and Molecular Mechanics in Biomolecular Systems publication trend

The graph below shows the total number of articles in quantum mechanics and molecular mechanics in biomolecular systems across all publications each year (not limited to Nature Index journals).

Technical terms

Quantum mechanics/molecular mechanics (QM/MM): Hybrid simulation approach that treats a region of interest with quantum mechanics while embedding it in a classical molecular mechanics environment to capture long-range effects at reduced computational cost.

Polarizable embedding: Multiscale framework in which induced dipoles or fluctuating charges in the classical region respond self-consistently to the quantum region’s electronic density, enhancing mutual polarisation.

Solvatochromic shift: Change in the absorption or emission wavelength of a chromophore due to interactions with its solvent environment.

Conical intersection: Point of degeneracy between electronic states on a potential-energy surface that facilitates ultrafast nonadiabatic transitions.

Proton-coupled electron transfer (PCET): Fundamental mechanism in which an electron and a proton are transferred either sequentially or concertedly, often governing photochemical and enzymatic processes.

References

1. Multistate, Polarizable QM/MM Embedding Scheme Based on the Direct Reaction Field Method: Solvatochromic Shifts, Analytical Gradients and Optimizations of Conical Intersections in Solution. Journal of Chemical Theory and Computation (2024).
2. UV-Resonance Raman Spectra of Systems in Complex Environments: A Multiscale Modeling Applied to Doxorubicin Intercalated into DNA. Journal of Chemical Information and Modeling (2023).
3. Fast Method for Excited-State Dynamics in Complex Systems and Its Application to the Photoactivation of a Blue Light Using Flavin Photoreceptor. The Journal of Physical Chemistry Letters (2023).