No free energy lunch

  title={No free energy lunch},
  author={Brian K. Shoichet},
  journal={Nature Biotechnology},
  • B. Shoichet
  • Published 1 October 2007
  • Biology
  • Nature Biotechnology
Prediction of a protein's affinity for a ligand has been improved through fundamental physical modeling. 
A systematic analysis of atomic protein–ligand interactions in the PDB
We compiled a list of 11 016 unique structures of small-molecule ligands bound to proteins representing 750 873 protein–ligand atomic interactions, and analyzed the frequency, geometry and the impact
A Systematic Analysis of Atomic Protein-Ligand Interactions in the PDB
A list of 11,016 unique structures of small-molecule ligands bound to proteins – 6,444 of which have experimental binding affinity - representing 750,873 protein-ligand atomic interactions is compiled, and the frequency, geometry and impact of each interaction type are analyzed.
Rapid Context-Dependent Ligand Desolvation in Molecular Docking
This work relates the Generalized-Born effective Born radii for every ligand atom to a fractional desolvation and uses this fraction to scale an atom-by-atom decomposition of the full transfer free energy.
Systematic analysis of the interactions driving small molecule-RNA recognition.
This study examined the Protein Data Bank to highlight privileged interactions underlying small molecule-RNA recognition, and finds that RNA recognition is driven mostly by stacking and hydrogen bonding interactions, while protein recognition is instead driven by hydrophobic effects.
Multiscale molecular dynamics of protein aggregation.
It is shown that a smart alternative to brute force and massive computation of uninteresting regions in the all atom potential energy surface is the consideration of a simplified reference potential, explored thoroughly in the relevant regions, combined with a free energy perturbation approach that transforms this simple representation to a full atom representation.
Implicit solvent methods for free energy estimation.
Protein conformational switches: from nature to design.
The purpose is to highlight examples that can potentially serve as platforms for the design of custom switches, and focuses on inducible conformational changes that are substantial enough to produce a functional response, yet are relatively simple, structurally well-characterized, and amenable to protein engineering efforts.
Recent trends and applications in 3D virtual screening.
It is proposed that the best way to advance the state of the art in 3D VS is to integrate complementary strategies in a single drug discovery pipeline, rather than to focus only on theoretical or computational improvements of individual techniques.
Intimate connections: Inositol pyrophosphates at the interface of metabolic regulation and cell signaling
  • S. Shears
  • Biology
    Journal of cellular physiology
  • 2018
This review pursues the idea that many of the biological effects of inositol pyrophosphates can be rationalized by their actions at the interface of cell signaling and metabolism that is essential to cellular and organismal homeostasis.


Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding.
It is concluded that the uncertainties from this source alone are sufficient to preclude the viability of current docking methodology for rank-ordering of diverse compounds in high-throughput virtual screening.
Calculation of absolute protein-ligand binding free energy from computer simulations.
  • H. Woo, B. Roux
  • Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
The present approach avoids the need to decouple the ligand from its surrounding (bulk solvent and receptor protein) as is traditionally performed in the double-decoupling scheme, and it is believed that the present formulation will be particularly useful when the solvation free energy of the ligands is very large.
Structural and genetic analysis of protein stability.
Substantial progress is being made in quantitating the interactions that determine and stabilize protein structures and in developing methods to engineer proteins of enhanced stability.
Free energy, entropy, and induced fit in host-guest recognition: calculations with the second-generation mining minima algorithm.
A strong correlation is observed between the changes in configurational energy andconfigurational entropy upon binding, resulting in near-linear compensation analogous to classical entropy-enthalpy compensation.
During recent decades it has become feasible to simulate the dynamics of molecular systems on a computer. The method of molecular dynamics (MD) solves Newton's equations of motion for a molecular
Computational design of antibody-affinity improvement beyond in vivo maturation
An iterative computational design procedure that focuses on electrostatic binding contributions and single mutants for enhancing and accelerating the development of protein reagents and therapeutics is presented.