Zooming across the Free-Energy Landscape: Shaving Barriers, and Flooding Valleys

Abstract

A robust importance-sampling algorithm for mapping free-energy surfaces over geometrical variables, coined meta-eABF, is introduced. This algorithm shaves the free-energy barriers and floods valleys by incorporating a history-dependent potential term in the extended adaptive biasing force (eABF) framework. Numerical applications on both toy models and nontrivial examples indicate that meta-eABF explores the free-energy surface significantly faster than either eABF or metadynamics (MtD) alone, without the need to stratify the reaction pathway. In some favorable cases, meta-eABF can be as much as five times faster than other importance-sampling algorithms. Many of the shortcomings inherent to eABF and MtD, like kinetic trapping in regions of configurational space already adequately sampled, the requirement of prior knowledge of the free-energy landscape to set up the simulation, are readily eliminated in meta-eABF. Meta-eABF, therefore, represents an appealing solution for a broad range of applications, especially when both eABF and MtD fail to achieve the desired result.

Potential of Matrix Metalloproteinase Inhibitors for the Treatment of Local Tissue Damage Induced by a Type P-I Snake Venom Metalloproteinase

“…Therefore, we turned to explicit-solvent molecular dynamics simulation using the CHARMM force field [44,45] to study the interactions between the compounds and the metalloproteinases in a more realistic manner. An enhanced sampling technique [46] was employed to obtain the free energy (potential of mean force) as a function of the distance between the hydroxamate or phosphonate group of each compound and the Zn 2+ ion. The resulting potential of mean force functions are shown in Figure 5.…”

“…The potentials of mean force were calculated by a hybrid of metadynamics and extended adaptive biasing force (meta-eABF) [46] using the implementation provided in the Colvars module of NAMD [60]. This algorithm uses the extended ABF method [61][62][63] to reduce free-energy barriers and calculate free energies (by integrating the potential of mean force), while a history-dependent potential term (metadynamics) [64] drives evolution of the system into less well-sampled regions of the transition coordinate.…”

Advances in enhanced sampling molecular dynamics simulations for biomolecules

“…There are also some other successful approaches in which diverse enhanced sampling methods are coupled to explore broader conformational space including replica-exchange metadynamics [135], meta-eABF [122], replica-exchange US [29], replica-exchange with collective variable tempering [136], replica averaged metadynamics [137], and MetaITS [138]. More details about their theoretical backgrounds, development process, and latest applications are reviewed in other articles [30,83,139,140].…”

Triggering Tautomerization of Curcumin by Confinement into Liposomes

“…The free‐energy landscape underlying curcumin partitioning was mapped for the enol and the keto forms, using the recent metadynamics‐extended adaptive biasing force (meta‐eABF) algorithm . The transition coordinate was defined as the projection onto the z ‐direction of Cartesian space, i. e ., the normal to the membrane, of the distance separating the centre of mass of curcumin from that of the lipid bilayer.…”