Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Mar 26;114(6):3353-65.
doi: 10.1021/cr4005988. Epub 2014 Jan 21.

Collective variable approaches for single molecule flexible fitting and enhanced sampling

Harish Vashisth  1 , Georgios Skiniotis, Charles Lee Brooks 3rd
Affiliations
Review

Collective variable approaches for single molecule flexible fitting and enhanced sampling

Harish Vashisth et al. Chem Rev. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
TAMD-generated conformational change in the activation loop of the insulin receptor kinase domain. (a) RMSD versus simulation time (ns) for the activation-loop (the A-loop), R-spine, C-spine, and Phe1151 with respect to the active crystal structure. Gray background in the plots indicates first ∼7 ns of MD equilibration, which is followed by ∼40 ns of TAMD. (b) Representative snapshots of IRKD from TAMD simulation are shown at various time-points with the A-loop in red, side-chains of Asp1150 and Phe1151 in cyan and blue, respectively. The conformation of the A-loop in the active crystal structure is shown as a black cartoon. The large panel in the center shows the conformations of IRKD with highlighted structural motifs: αC-helix, nucleotide-binding loop, and the activation loop from TAMD simulation at t = 7.59 (red), 17.09, 22.89, 40.09, and 47.00 ns (blue). Arrow directions guide along the increasing simulation time. Adapted with permission from ref (167). Copyright 2012 Elsevier.
Figure 2
Figure 2
TAMD-generated conformational change in the C-terminus of the B-chain of each insulin. (A) Traces (T-insulin, black; R-insulin, cyan) of the root-mean-squared deviation (RMSD) and buried surface area (BSA) versus simulation time (ns) are shown for each insulin/IRΔβ complex. Circled digits indicate the following: (①) RMSD of the C-terminus (residue B21–B30) of the B-chain of each insulin. For RMSD computation, the insulin molecules were aligned based upon the residues of each A- and B-chain (A1–A21 and B1–B20; Cα); (②) BSA between the C-terminus of the B-chain (residues B21–B30) of each insulin and rest of the insulin molecules; (③) BSA between each insulin molecule (except the B-chain residues B21–B30) and the L1 domain; and (④) BSA between CT and the L1 domain. Horizontal lines indicate the values measured in the IRΔβ crystal structure (PDB code 3LOH) except the dotted horizontal lines that are arbitrarily drawn for guidance. (B) Conformational change in the C-terminus of the B-chain of each insulin is highlighted. Representative snapshots of each insulin (transparent blue), CT (transparent red), and the L1 and CR domains of IRΔβ (transparent white) are shown at various time-points of respective TAMD simulations. The residues FB24, FB25, and YB26 are shown in sticks and labeled in the first snapshot for each insulin/IRΔβ complex. Initial positions of CT are different (from the crystal structure) for each insulin/IRΔβ complex because TAMD trajectories were started based upon the Monte Carlo (MC) docked and MD-equilibrated structural models of each insulin/IRΔβ complex. Some of the terminal residues of CT spontaneously fold/unfold during TAMD trajectories. Adapted with permission from ref (169). Copyright 2013 John Wiley & Sons, Inc.
Figure 3
Figure 3
MD and TAMD simulation data for RGS4 runs with initial coordinates from PDB code 1AGR. (a and b) Overlay of cartoon representations of apo-RGS4 (red, beginning; blue, end of simulations). All helices of RGS4, except the α5–α6 pair, are shown in white cartoons. (c) The Cα-RMSD traces with reference to starting conformations. (d) Buried surface area (BSA) between the α5–α6 helix pair and the rest of RGS4. Adapted with permission from ref (170). Copyright 2013 American Chemical Society.
Figure 4
Figure 4
MDFF versus TAMD-assisted MDFF (TAMDFF) fitting of adenylate kinase in explicit solvent. (A; top panel) Schematic representation of the simulation domain (29416 atoms) of the adenylate kinase (ADK) as viewed along the z-axis: starting docked closed-conformation of ADK (black cartoon), 5 Å resolution target map (blue surface), water molecules (wireframe), and ions (spheres). (A; bottom panel) Subdomain partitions of ADK are shown for the TAMD simulation. Each sphere represents the center-of-mass (COM) of a mutually exclusive subdomain. Entire ADK structure was divided into 9 subdomains. (B) Top and bottom panels, respectively, show the Cα-RMSD traces from the known initial and final crystal conformations of ADK. The black trace is from an MDFF simulation, while the traces of other color are from six independent TAMD-assisted MDFF (TAMDFF) simulations. Initial/final correlation coefficients for all seven simulations are shown in the bottom panel. (C) Cartoon representations of two different views of the overlay of final conformations generated via MDFF and TAMDFF simulations are shown. Cartoon colors are the same as the RMSD traces in panel B. Adapted with permission from ref (111). Copyright 2012 Elsevier.
Figure 5
Figure 5
Conformational change in the Gα-subunit of a GTP-binding protein (G-protein) studied via MDFF and TAMD simulations. (A) Cartoon representations for MDFF fitting of Gα at 5 Å target-map resolution: initial docked open-state crystal conformation (white cartoon; left panel), final conformations generated via two independent 20-ns MDFF simulations (red and green cartoons; middle panels), and the known target closed-state crystal conformation with perfect correlation coefficient of 1.0 (black cartoon; boxed right-most panel). The Cα-RMSD (with respect to the final crystal structure) traces for each 20-ns MDFF run are shown in panel B. (B) Representative snapshots from a 40-ns TAMD simulation of Gα are shown at various time-points during the simulation. TAMD-generated conformation is shown in cyan, and the known closed-state crystal structure conformation is in black. The Cα-RMSD (with respect to the final crystal structure) trace from the ∼40-ns TAMD simulation is shown in the central right-panel along with the RMSD trace from an unbiased ∼36-ns explicit-solvent MD simulation of Gα. Adapted with permission from ref (111). Copyright 2012 Elsevier.
Figure 6
Figure 6
Explicit-solvent MDFF versus TAMDFF fitting of helix-44 (H44) from the mature small (40S) eukaryotic ribosomal subunit into an experimental map of a pre-40S maturation intermediate. (A) Schematic representation of the simulation domain (208390 atoms) of solvated H44 as viewed along the z-axis: starting docked conformation of H44 (black cartoon), ∼18 Å resolution target map (cyan surface), water molecules (wireframe), and Mg2+ ions (green spheres). The additional globular blobs of density near H44 are from some accessory factor proteins (not modeled here). (B) The backbone (P-atoms) RMSD traces from the known initial crystal conformation of H44 (PDB code 3U5F). The black trace is from an MDFF simulation, while the traces of other color are from five independent TAMDFF simulations. Initial/final correlation-coefficients for all six simulations are also shown. Inset highlights the RMSD traces in early parts of MDFF and TAMDFF simulations. (C) Map-docked cartoon representations are shown for two different views of the overlay of final conformations generated via MDFF and TAMDFF simulations. Adapted with permission from ref (112). Copyright 2013 American Chemical Society.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Grant B. J.; Gorfe A. A.; McCammon J. A. Curr. Opin. Struct. Biol. 2010, 20, 142. - PMC - PubMed
    1. Karplus M.; Petsko G. A. Nature 1990, 347, 631. - PubMed
    1. Karplus M.; McCammon J. A. Nat. Struct. Mol. Biol. 2002, 9, 646. - PubMed
    1. Karplus M.; Kuriyan J. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 6679. - PMC - PubMed
    1. Adcock S. A.; McCammon J. A. Chem. Rev. 2006, 106, 1589. - PMC - PubMed

Publication types

LinkOut - more resources