Enhanced conformational sampling to visualize a free-energy landscape of protein complex formation

Abstract

We introduce various, recently developed, generalized ensemble methods, which are useful to sample various molecular configurations emerging in the process of protein–protein or protein–ligand binding. The methods introduced here are those that have been or will be applied to biomolecular binding, where the biomolecules are treated as flexible molecules expressed by an all-atom model in an explicit solvent. Sampling produces an ensemble of conformations (snapshots) that are thermodynamically probable at room temperature. Then, projection of those conformations to an abstract low-dimensional space generates a free-energy landscape. As an example, we show a landscape of homo-dimer formation of an endothelin-1-like molecule computed using a generalized ensemble method. The lowest free-energy cluster at room temperature coincided precisely with the experimentally determined complex structure. Two minor clusters were also found in the landscape, which were largely different from the native complex form. Although those clusters were isolated at room temperature, with rising temperature a pathway emerged linking the lowest and second-lowest free-energy clusters, and a further temperature increment connected all the clusters. This exemplifies that the generalized ensemble method is a powerful tool for computing the free-energy landscape, by which one can discuss the thermodynamic stability of clusters and the temperature dependence of the cluster networks.

Autoinhibition can identify rare driver mutations and advise pharmacology

“…[40][41][42][43][44][45][46][47][48][49][50][51][52] The landscape is not static. [40][41][42][43][44][45][46][47][48][49][50][51][52] The landscape is not static.…”

“…The free energy landscape portrays all protein (or biological macromolecule) states; some are highly populated thus observed, others only sparsely populated thus hidden. [40][41][42][43][44][45][46][47][48][49][50][51][52] The landscape is not static. 53 A change in conditions, such as overexpression, mutations, post-translational modifications, or presence of other molecules, such as phospholipids, or cholesterol, or bound water molecules or ions, can alter the relative populations of these states.…”

Temperature–pressure shuffling outlier flooding method enhances the conformational sampling of proteins

“…Recently, most of the proposed methodologies have been implemented in the several well‐established MD packages. For details of the above methodologies, there are several review papers …”

“…For details of the above methodologies, there are several review papers. [20][21][22] In addition to the well-established methods, we have proposed several enhanced conformational sampling methods that have no external bias or restraint. [23,24] In more detail, the following cycle of conformational resampling (step 1 and step 2) is simply repeated.…”

Temperature–Energy-space Sampling Molecular Dynamics: Deterministic, Iteration-free, and Single-replica Method utilizing Continuous Temperature System

“…These two MD methods are based on MC methods [13][14][15]. See reviews [16][17][18] for other methods, various applications, and related topics. Recent developments can be founded in literature [19][20][21][22][23][24].…”