Decrypting Integrins by Mixed-Solvent Molecular Dynamics Simulations

Abstract

Integrins are a family of α/β heterodimeric cell surface adhesion receptors which are capable of transmitting signals bidirectionally across membranes. They are known for their therapeutic potential in a wide range of diseases. However, the development of integrin-targeting medications has been impacted by unexpected downstream effects including unwanted agonist-like effects. Allosteric modulation of integrins is a promising approach to potentially overcome these limitations. Applying mixed-solvent molecular dynamics (MD) simulations to integrins, the current study uncovers hitherto unknown allosteric sites within the integrin α I domains of LFA-1 (αLβ2; CD11a/CD18), VLA-1 (α1β1; CD49a/CD29), and Mac-1 (αMβ2, CD11b/CD18). We show that these pockets are putatively accessible to small-molecule modulators. The findings reported here may provide opportunities for the design of novel allosteric integrin inhibitors lacking the unwanted agonism observed with earlier as well as current integrin-targeting drugs.

Elucidating the role of water in collagen self-assembly by isotopically modulating collagen hydration

“…Controllable and tunable macroscopic properties might be achieved by subtle changes in the solvent isotopic composition instead of altering the chemical structure of a biomaterial’s building blocks. Furthermore, minimal changes of the solvent conditions can induce the structural rearrangement of a protein (without disrupting its secondary structure) to unveil novel allosteric pockets, hence rendering the target as druggable ( 77 ). Finally, altered water–collagen interactions are believed to play a role in several age-related diseases ( 8 , 78 – 80 ), and to partially contribute to tissue dysfunction in these disorders.…”

Unlocking novel therapies: cyclic peptide design for amyloidogenic targets through synergies of experiments, simulations, and machine learning

“…Alternatively, by tweaking the environmental conditions through mild solvent alteration, e.g. by replacing water with D 2 O 98 or by adding organic compounds, 99,100 one can delicately alter the conformational landscape of the protein to reveal new (allosteric) druggable pockets without disturbing the protein's secondary structure. We refer the interested reader to a series of reviews on peptide-based strategies to interfere with protein misfolding and aggregation, 101,102 a review on the therapeutic potential of cyclic 90 and bicyclic peptides.…”

Probing the conformational dynamics of an Ago–RNA complex in water/methanol solution

“…By eqn (1), the desired number of methanol molecules in the simulation box, have been randomly inserted using gmx insert-molecules command, at a distance larger than the sum of van der Waals radii of the solute and solvent atoms. 30 The solvated box has a total of 21 950 and 10 985 molecules of water and methanol respectively, corresponding to a water/MeOH molar ratio of 67% Taking V VdW water and V VdW MeOH equal to 19.51 and 36.75 Å 3 respectively, the mixed solvent box has a water/MeOH volume ratio of B50%. After solvation a total of 8 Na + ions were added to set both systems electrically neutral.…”

“…In general, for protein complexes, computational studies such as molecular docking and molecular dynamics simulations performed in different solvents, can provide information related to specific site interactions between a protein and small ligand as well as protein and protein, particularly in the field of drug design [25][26][27] or to detect cryptic binding sites in proteins. [28][29][30] Considering protein RNA/DNA complexes, the role of aminoacids and nucleobases related to the strength of proteinoligonucleotide interactions, was also investigated using molecular dynamics simulations in methanol. 31 Our study provides new insights into the relationship between seed and supplementary duplex mobility.…”