Overcoming Free-Energy Barriers with a Seamless Combination of a Biasing Force and a Collective Variable-Independent Boost Potential

Amid collective-variable (CV)-based importance-sampling algorithms, a hybrid of the extended adaptive biasing force and the well-tempered metadynamics algorithms (WTM-eABF) has proven particularly cost-effective for exploring the rugged free-energy landscapes that underlie biological processes. However, as an inherently CV-based algorithm, this hybrid scheme does not explicitly accelerate sampling in the space orthogonal to the chosen CVs, thereby limiting its efficiency and accuracy, most notably in those cases where the slow degrees of freedom of the process at hand are not accounted for in the model transition coordinate. Here, inspired by Gaussian-accelerated molecular dynamics (GaMD), we introduce the same CV-independent harmonic boost potential into WTM-eABF, yielding a hybrid algorithm coined GaWTM-eABF. This algorithm leans on WTM-eABF to explore the transition coordinate with a GaMD-mollified potential and recovers the unbiased free-energy landscape through thermodynamic integration followed by proper reweighting. As illustrated in our numerical tests, GaWTM-eABF effectively overcomes the free-energy barriers in orthogonal space and correctly recovers the unbiased potential of mean force (PMF). Furthermore, applying both GaWTM-eABF and WTM-eABF to two biologically relevant processes, namely, the reversible folding of (i) deca-alanine and (ii) chignolin, our results indicate that GaWTM-eABF reduces the uncertainty in the PMF calculation and converges appreciably faster than WTM-eABF. Obviating the need of multiple-copy strategies, GaWTM-eABF is a robust, computationally efficient algorithm to surmount the free-energy barriers in orthogonal space and maps with utmost fidelity the free-energy landscape along selections of CVs. Moreover, our strategy that combines WTM-eABF with GaMD can be easily extended to other biasing-force algorithms.

Automated summary

GaWTM-eABF is a hybrid algorithm that introduces the GaMD softened potential into WTM-eABF, effectively overcoming free-energy barriers in orthogonal space and accurately recovering unbiased free-energy landscape. Numerical tests demonstrate that GaWTM-eABF reduces uncertainty in PMF calculation and converges faster than WTM-eABF.