Multiscale investigation of chemical interference in proteins

Abstract

We developed a multiscale approach (MultiSCAAL) that integrates the potential of mean force obtained from all-atomistic molecular dynamics simulations with a knowledge-based energy function for coarse-grained molecular simulations in better exploring the energy landscape of a small protein under chemical interference such as chemical denaturation. An excessive amount of water molecules in all-atomistic molecular dynamics simulations often negatively impacts the sampling efficiency of some advanced sampling techniques such as the replica exchange method and it makes the investigation of chemical interferences on protein dynamics difficult. Thus, there is a need to develop an effective strategy that focuses on sampling structural changes in protein conformations rather than solvent molecule fluctuations. In this work, we address this issue by devising a multiscale simulation scheme (MultiSCAAL) that bridges the gap between all-atomistic molecular dynamics simulation and coarse-grained molecular simulation. The two key features of this scheme are the Boltzmann inversion and a protein atomistic reconstruction method we previously developed (SCAAL). Using MultiSCAAL, we were able to enhance the sampling efficiency of proteins solvated by explicit water molecules. Our method has been tested on the folding energy landscape of a small protein Trp-cage with explicit solvent under 8M urea using both the all-atomistic replica exchange molecular dynamics and MultiSCAAL. We compared computational analyses on ensemble conformations of Trp-cage with its available experimental NOE distances. The analysis demonstrated that conformations explored by MultiSCAAL better agree with the ones probed in the experiments because it can effectively capture the changes in side-chain orientations that can flip out of the hydrophobic pocket in the presence of urea and water molecules. In this regard, MultiSCAAL is a promising and effective sampling scheme for investigating chemical interference which presents a great challenge when modeling protein interactions in vivo.

Kinetic and structural characterization of thermostabilized mutants of human carbonic anhydrase II

“…This observation can be partly explained by urea denaturation thought to occur through unfolding of the hydrophobic core of the protein. It has also been pointed out that urea can interact with the protein through electrostatic, van der Waals interactions, and indirectly through the disruption of water structure (Samiotakis et al, 2010;Wang et al, 2011). Since the mutations reported here were all on the surface and active site of the protein, that is not in the core, the denaturation resulted in similar effects in the wildtype and mutant enzymes.…”

Structure, function, and folding of phosphoglycerate kinase are strongly perturbed by macromolecular crowding

“…The thermodynamic properties of PGK were studied at the volume fractions of crowder Ficoll 70 ϕ c ¼ 0%, ϕ c ¼ 25%, and ϕ c ¼ 40% by coarse-grained molecular simulation (by convention, the volume fraction of crowders is presented as a percentage of total volume; i.e., ϕ c ¼ 25% corresponds to 0.25 of the total volume). Several represented coarse-grained structures were reconstructed to all-atomistic protein models for illustration by using SCAAL (15,22).…”

“…The crystal structure ensemble C had 0.05 ≤ χ ≤ 0. To better illustrate the structural differences among ensemble conformations of PGK in atomistic detail, we reconstructed the coarse-grained protein models of the C, CC, and Sph states into all-atomistic protein models using the reconstruction algorithm SCAAL (side chain−C α to all-atom) (15,22) (Fig. 4 A-C).…”

Harnessing Structural Data of Insulin and Insulin Receptor for Therapeutic Designs

“…For future study of the insulin-stimulated conformational switch of full-length IR, we recommend the following methods that have successfully been applied on related/other systems: MD simulations [50], harmonic oscillator model to estimate kinetics parameters [19], normal mode analysis (NMA) to determine rotations [52], and multi-scale simulation [53] approach that combines coarse-grained and all-atomistic MD simulations. NMA on the IR ectodomain (PDB: 3LOH_E) suggests that the N-terminal of L1 domain and the CR domain have the potential to move closer to each other (Fig.…”