Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics

Abstract

We show how to apply the method of temperature-accelerated molecular dynamics (TAMD) in collective variables [Maragliano L, Vanden-Eijnden E (2006) Chem Phys Lett 426:168-175] to sample the conformational space of multidomain proteins in all-atom, explicitly solvated molecular dynamics simulations. The method allows the system to hyperthermally explore the free-energy surface in a set of collective variables computed at the physical temperature. As collective variables, we pick Cartesian coordinates of centers of contiguous subdomains. The method is applied to the GroEL subunit, a 55-kDa, three-domain protein, and HIV-1 gp120. For GroEL, the method induces in about 40 ns conformational changes that recapitulate the t → r 00 transition and are not observed in unaccelerated molecular dynamics: The apical domain is displaced by 30 Å, with a twist of 90°relative to the equatorial domain, and the root-mean-squared deviation relative to the r 00 conformer is reduced from 13 to 5 Å, representing fairly high predictive capability. For gp120, the method predicts both counterrotation of inner and outer domains and disruption of the so-called bridging sheet. In particular, TAMD on gp120 initially in the CD4-bound conformation visits conformations that deviate by 3.6 Å from the gp120 conformer in complex with antibody F105, again reflecting good predictive capability. TAMD generates plausible all-atom models of the so-far structurally uncharacterized unliganded conformation of HIV-1 gp120, which may prove useful in the development of inhibitors and immunogens. The fictitious temperature employed also gives a rough estimate of 10 kcal∕mol for the free-energy barrier between conformers in both cases.biophysical simulation | domain motion | free energy | collective variables S ince Koshland's introduction of the concept of "induced fit" (1), it is well accepted that conformational changes upon ligand binding underlie a substantial fraction of protein functionality (2, 3). Crystal structures of hundreds of proteins in both apo and liganded states often display evidence for motion of domains relative to one another over length scales characteristic of the domains themselves (4). Crystallographic conformers of the same protein, however, cannot provide much insight into the detailed mechanism of conformational change, especially if more than one hinge or other flexible element is involved. Even worse, there are many multidomain proteins for which only a single crystallographic conformer exists despite functional requirements for multiple conformers. On top of obscuring the structural biology of many multidomain proteins, often a single crystallographic conformer is too narrow a basis upon which to design molecules that act as allosteric effectors: agents that stabilize either active or inhibitory conformations by binding to sites other than those used by the primary ligands. It has therefore become attractive to probe the details of protein conformational dynamics using simulation methods, such as molecular dynamics (MD) and relat...

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

“…We attempted to enhance the sampling in our TIP4P-Ew simulations using temperatureaccelerated molecular dynamics (TAMD) (58,59) to determine whether the sliding motion is sensitive to the choice of water model. We accelerated the transition rate between system states by imposing a TAMD restraint on a pair of spacer residues, without directly biasing the motion of the FG motif (Methods).…”

Sampling reactive pathways with random walks in chemical space: Applications to molecular dissociation and catalysis

“…Note that the energies of minima and TSs are approximate; further refinement by methods such as CI-NEB would yield more accurate geometries and energies. As noted in the text, the physical isomerization between cis-and trans-HCOH is not observed in our simulations; our graphbased scheme is aimed at sampling different chemistry in the reactants and products, although use of temperatureaccelerated sampling 64,71,72 would help improve sampling of the configurational space for a given set of chemical species at either end-point of the reaction string. .…”

“…Furthermore, our simulations did not appear to sample a reactive pathway which corresponded to the interesting "roaming" mechanism. Both of these problems are symptomatic of limited sampling in both end-point configurational space and path-variable space, and are not inherent issues with our overall graph-based scheme; for example, the sampling of end-point configurations could be straightforwardly improved by using temperature-accelerated sampling methodologies, 64,71,72 and similar enhanced sampling can be envisaged for path variables. These are both avenues which will be explored in the near future.…”

“…Clearly, leaving this sampling of isomers to chance in the graph rearrangement step is not desirable. Instead, we are now exploring the use of temperature-accelerated sampling methods for the end-point configurations to circumvent this problem in order to fully sample both di↵erent chemical isomers and di↵erent conformations; 71,72 for example, in the present case, it is straightforward to see that enhanced sampling along the HCOH torsional coordinate will increase the sampling of the cis-trans isomerization. Furthermore, a similar temperature-accelerated scheme can be formulated for the path variables; this is one route to improved sampling in path-space which would be expected to aid in the sampling of alternative reaction paths, such as the "roaming" mechanism noted above.…”

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“…20. Other methods do without an external bias altogether, like temperatureaccelerated molecular dynamics (MD) (21), in which an artificially large friction is applied to a set of CVs to ensure that they evolve slowly compared with the atomic motions. This list is by no means exhaustive; for a more thorough review see for example ref.…”