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WIREs Comput Mol Sci
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Frontiers in free‐energy calculations of biological systems

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In a matter of three decades, free‐energy calculations have emerged as an indispensable tool to tackle deep biological questions that experiment alone has left unresolved. In spite of recent advances on the hardware front that have pushed back the limitations of brute‐force molecular dynamics simulations, opening the way to time and size scales hitherto never attained, they represent a cogent alternative to access with unparalleled accuracy the thermodynamics and possibly the kinetics that underlie the complex processes of the cell machinery. From a pragmatic perspective, the present review draws a picture of how the field has been shaped and invigorated by milestone developments, application, and sometimes rediscovery of foundational principles laid down years ago to reach new frontiers in the exploration of intricate biological phenomena. Through a series of illustrative examples, distinguishing between alchemical and geometrical transformations, it discusses how far free‐energy calculations have come, what are the current hurdles they have to overcome, and the challenges they are facing for tomorrow. WIREs Comput Mol Sci 2014, 4:71–89. doi: 10.1002/wcms.1157 This article is categorized under: Molecular and Statistical Mechanics > Free Energy Methods
Typical timescales spanned by biological processes of the cell machinery. From left to right—Translational and orientational relaxation of water on the picosecond timescale; Spontaneous binding of zanamivir or Relenza, an inhibitor of neuraminidase in the A/H1N1 virus; Folding of the villin headpiece subdomain, a fast‐folding protein formed by 35 amino acids; and Conformational transition in the mitochondrial transporter of adenosine di‐ and triphosphate.
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Synoptic description of a Hamiltonian‐hopping stratified free‐energy perturbation calculation, wherein the hydration free energy of benzene is measured by decoupling reversibly the latter from the aqueous environment. The replicas corresponding to distinct Hamiltonians and configurations, distributed onto an array of computing cores. After a predefined number of steps, two replicas are randomly swapped. A Metropolis‐Hastings‐like criterion is utilized to determine whether the swap is accepted or rejected.
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Framework used to characterize the binding of proline‐rich peptide p41 (stick representation colored by atom type) to the src homology domain 3 of the Abl kinase (secondary‐structure representation). For both the protein and the ligand, three groups of atoms are chosen arbitrarily, forming two triplets, { P1, P2, P3 } and { L1, L2, L3 }, respectively. The position of ligand p41 with respect to the protein is defined by means of the set of the spherical coordinates {r, θ, and ϕ}. Its relative orientation is expressed using the three Euler angles {Θ, Φ, and Ψ}.
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Intricacy of the biological objects forming the cell machinery. Shown in this artistic composite view is the translocon (magenta), an integral membrane protein, to which the ribosome (green) is anchored. The exit tunnel of the latter forms with the former a continuous translocation channel along which the synthesized peptide chain is conveyed. Free‐energy calculations help understand how the hospitable environment of the translocon not only reduces the cost for translocating charged amino acids—e.g., an arginine residue depicted in van der Waals spheres, but also the gain for translocating hydrophobic ones, resulting in a compressed hydrophobic scale.
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