A conformational factorisation approach for estimating the binding free energies of macromolecules

Abstract

Publisher's copyright statement:Additional information: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. We present a conformational factorization approach. The theory is based on a superposition partition function, where the partition function is written as a sum over contributions from local minima. The factorisation greatly reduces the number of minima that need to be considered, by employing the same local configurations for groups that are sufficiently distant from the binding site. The theory formalises the conditions required to analyse how our definition of the binding site region affects the free energy difference between the apo and holo states. We employ basin-hopping parallel tempering to sample minima that contribute significantly to the partition function, and calculate the binding free energies within the harmonic normal mode approximation. A further significant gain in efficiency is achieved using a recently developed local rigid body framework in both the sampling and the normal mode analysis, which reduces the number of degrees of freedom. We benchmark this approach for human aldose reductase (PDB code 2INE). When varying the size of the rigid region, the free energy difference converges for factorisation of groups at a distance of 14Å from the binding site, which corresponds to 80% of the protein being locally rigidified. This approach is likely to be useful for estimating the binding free energy of protein-ligand complexes.

Perspective: Insight into reaction coordinates and dynamics from the potential energy landscape

“…47 Significant efficiency gains for global optimisation in biomolecules can be obtained if large moves in configuration space can be proposed without causing groups of bonded atoms to overlap. Here, a group rotation scheme has been successfully applied, [48][49][50] and this approach can be combined with local rigidification of arbitrary sets of atoms, 51 using angleaxis coordinates. 52,53 For two peptides, where benchmarking statistics can still be obtained for less efficient approaches, local rigidification improved the mean first encounter times for the global minima by up to a factor of 4.…”

Global Materials Structure Search with Chemically Motivated Coordinates

“…This would not only bias the simulation towards the truly targeted structures, but also allow for an efficient sampling of system sizes and complexities that are otherwise not tractable. An incorporation of corresponding The crucial relevance of the trial structure generation step has already been emphasized in earlier, system-specific work, 6,7 where for example simple group rotations within proteins 8 or clusters 3 already led to significant gains in sampling efficiency. Additionally, internal coordinates have shown to be beneficial for structures connected by double-ended pathways.…”

Protein Structure Prediction: Assembly of Secondary Structure Elements by Basin‐Hopping

“…Dihedral angle moves are applied to all amino acids in the chain. For the side chains we employ group rotation moves as described in [39]. Unlike in previous work, 8-11, 13-15, 18 where the dihedral angles of randomly chosen residues along the chain were perturbed, we now apply dihedral angle changes to three to five contiguous residues.…”

“…Third, we apply generalized rotation moves to sample the rotameric states of protein side chains. 39 This scheme allows arbitrary groups of atoms to be rotated about an axis defined by a bond vector, maintaining maximum flexibility without introducing reliance on standard topologies. For instance, for a Lys side chain three such rotatable groups are defined, where atoms are rotated about the C α −C β , C β −C γ and C γ −C δ bonds.…”