We introduce a rare-event sampling scheme, named Markovian Weighted Ensemble Milestoning (M-WEM), which inlays a weighted ensemble framework within a Markovian milestoning theory to efficiently calculate thermodynamic and kinetic properties of long-time-scale biomolecular processes from short atomistic molecular dynamics simulations. M-WEM is tested on the Muller−Brown potential model, the conformational switching in alanine dipeptide, and the millisecond time-scale protein−ligand unbinding in a trypsin−benzamidine complex. Not only can M-WEM predict the kinetics of these processes with quantitative accuracy but it also allows for a scheme to reconstruct a multidimensional free-energy landscape along additional degrees of freedom, which are not part of the milestoning progress coordinate. For the ligand−receptor system, the experimental residence time, association and dissociation kinetics, and binding free energy could be reproduced using M-WEM within a simulation time of a few hundreds of nanoseconds, which is a fraction of the computational cost of other currently available methods, and close to 4 orders of magnitude less than the experimental residence time. Due to the high accuracy and low computational cost, the M-WEM approach can find potential applications in kinetics and free-energy-based computational drug design.

The Hoogsteen (HG) base pairing conformation, commonly observed in damaged and mutated DNA helices, facilitates DNA repair and DNA recognition. The free energy difference between HG and Watson–Crick (WC) base pairs has been computed in previous studies. However, the mechanism of the conformational transition is not well understood. A detailed understanding of the process of WC to HG base pair transition can provide a deeper understanding of DNA repair and recognition. In an earlier study, we explored the free energy landscape for this process using extensive computer simulation with the CHARMM36 force field. In this work, we study the impact of force field models in describing the WC to HG base pairing transition using meta-eABF enhanced sampling, quasi-harmonic entropy calculation, and nonbonded energy analysis. The secondary structures of both base pairing forms and the topology of the free energy landscapes were consistent over different force field models, although the relative free energy, entropy, and the interaction energies tend to vary. The relative stability of the WC and HG conformations is dictated by a delicate balance between the enthalpic stabilization and the reduced entropy of the structurally rigid HG structure. These findings highlight the impact that subtleties in force field models can have on accurately modeling DNA base pair dynamics and should stimulate further computational investigations into other dynamically important motions in DNA.

models can be built where the position of paramagnetic center is adjusted such as to reproduce all PRE-extracted distances. On the other hand, K10C-and E15C-MTSL adopt unusual conformations with MTSL tag packed at the periphery of the protein hydrophobic core (accompanied by visible distortions of the fold). This behavior causes poor agreement between the predicted and experimental PREs, suggesting that force-field parameters of the MTSL tag may need an improvement. Support: SPbU grant 51142660.

The Hoogsteen (HG) base pairing (bp) conformation, commonly observed in damaged and mutated DNA helix, facilitates DNA repair mechanism and DNA recognition by proteins and small molecules. The free energy difference of HG and Watson-Crick (WC) base pairs has been computed in previous computational studies. But, the mechanism of the conformational transition is not well understood. A detailed understanding of the process of WC to HG base pair transition can provide deeper understanding of DNA repair and recognition. In an earlier study, we explored the free energy landscape for this process using extensive computer simulation with CHARMM36 force field for the nucleic acid. In this work, we study the impact of force field models in describing the WC to HG base pairing transition using the meta-eABF enhanced sampling, quasi-harmonic entropy calculation, and non-bonded energy analysis. The secondary structures of the both base pairing forms and the topology of the free energy landscapes were consistent over different force field models, although the relative free energy, entropy and the interaction energies tend to vary. The relative stability of WC and HG conformation is dictated by a delicate balance between the enthalpic stabilization and the reduced entropy of the structurally rigid HG structure. These findings provide a holistic view on the impact of force fields on the DNA base pair dynamics leading to the formation of HG conformation and will facilitate future computational investigations of DNA repair and recognition mechanism in physiologically relevant conditions.