Partner-Specific Prediction of Protein-Dimer Stability from Unbound Structure of Monomer

Paola

et al. 2022

ACS Omega

Self Cite

At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its diffusion, but the need of purposed drugs is emerging as a core target of the fight against COVID19. In this respect, the repurposing of drugs has already led to discovery of drugs thought to reduce the effects of the cytokine storm, but still a drug targeting the spike protein, in the infection stage, is missing. In this work, we present a multifaceted computational approach strongly grounded on a biophysical modeling of biological systems, so to disclose the interaction of the SARS-CoV2 spike protein with ACE2 with a special focus to an allosteric regulation of the spike–ACE2 interaction. Our approach includes the following methodologies: Protein Contact Networks and Network Clustering, Targeted Molecular Dynamics, Elastic Network Modeling, Perturbation Response Scanning, and a computational analysis of energy flow and SEPAS as a protein-softness and monomer-based affinity predictor. We applied this approach to free (closed and open) states of spike protein and spike–ACE2 complexes. Eventually, we analyzed the interactions of free and bound forms of spike with hepcidin (HPC), the major hormone in iron regulation, recently addressed as a central player in the COVID19 pathogenesis, with a special emphasis to the most severe outcomes. Our results demonstrate that, compared with closed and open states, the spike protein in the ACE2-bound state shows higher allosteric potential. The correspondence between hinge sites and the Allosteric Modulation Region (AMR) in the S-ACE complex suggests a molecular basis for hepcidin involvement in COVID19 pathogenesis. We verify the importance of AMR in different states of spike and then study its interactions with HPC and the consequence of the HPC-AMR interaction on spike dynamics and its affinity for ACE2. We propose two complementary mechanisms for HPC effects on spike of SARS-CoV-2; (a) HPC acts as a competitive inhibitor when spike is in a preinfection state (open and with no ACE2), (b) the HPC-AMR interaction pushes the spike structure into the safer closed state. These findings need clear molecular in vivo verification beside clinical observations.

Section: Materials and Methodsmentioning

confidence: 99%

Biophysical Insight into the SARS-CoV2 Spike–ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach

Paola

et al. 2022

ACS Omega

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“…To consider topological and structural properties of PBP regions, the accessible surface area (ASA) of the central region and surrounding region of the proposed PBP was computed in terms of total ASA and hydrophobic and polar fraction. We had introduced complex stability code (CSC) to include inter-residue distance ( D ) of PBP residues, their relative protrusion (rP), and the average affinity of the residues for protein binding (AAB) in our computations as a unique metric (eq ). AAB is derived from the affinity of residues for interacting with other residues in docked structures, which was reported previously .…”

Section: Methodsmentioning

confidence: 99%

“…We supposed that the PBP region on each subunit of the intended protein heterodimer, members of the affinity benchmark, was composed of two parts; 18 a central region that is the direct contact site of interacting subunits and a surrounding region which engulfs the direct contact site on one subunit. If the distance between any atom of a residue on subunit A and any atom on subunit B was smaller than 4 Å, then such residue resided on the central region of PBP on subunit A.…”

Section: Definition Of Protein Binding Patchmentioning

confidence: 99%

“…More information about the possible meaning of such metrics in the field of protein structure was presented in our recent article. 18 In brief, VM, DM, and TT indicate the presence of some isolated spots in the PBP region where their constituent residues have similar CSCs.…”

Section: Classification Of Affinity Benchmark Dimers Based On Their Pbpsmentioning

confidence: 99%

“…All of the mentioned methods require 3D structure of the complex, and additionally, in many cases they need to compute various descriptors of protein structures. Our previous introduced method predicts the PISA-computed dimer stability in the crystalline state using many descriptors . In the current study, we introduce a method to predict experimentally measured affinity between subunits by estimating the mechanical softness of the proposed binding site region on just one subunit of the intended complex.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Complex Stability is Encoded in Binding Patch Softness: a Monomer-Based Approach to Predict Inter-Subunit Affinity of Protein Dimers

2019

J. Proteome Res.

Self Cite

Knowledge about the structure and stability of protein–protein interactions is vital to decipher the behavior of protein systems. Prediction of protein complexes’ stability is an interesting topic in the field of structural biology. There are some promising published computational approaches that predict the affinity between subunits of protein dimers using 3D structures of both subunits. In the current study, we classify protein complexes with experimentally measured affinities into distinct classes with different mean affinities. By predicting the mechanical stiffness of the protein binding patch (PBP) region on a single subunit, we successfully predict the assigned affinity class of the PBP in the classification step. Now to predict the experimentally measured affinity between protein monomers in solution, we just need the 3D structure of the suggested PBP on one subunit of the proposed dimer. We designed the SEPAS software and have made the software freely available for academic non-commercial research purposes at “”. SEPAS predicts the stability of the intended dimer in a classwise manner by utilizing the computed mechanical stiffness of the introduced binding site on one subunit with the minimum accuracy of 0.72.

Effect of Lithium Drug on Binding Affinities of Glycogen Synthase Kinase-3 β to Its Network Partners: A New Computational Approach

Rouhani

2021

J. Chem. Inf. Model.

Self Cite

Finding new methods to study the effect of small molecules on protein interaction networks provides us with invaluable tools in the fields of pharmacodynamics and drug design. Lithium is an antimanic drug that has been used for the treatment of bipolar disorder for more than 60 years. Here, we utilized a new approach to study the effect of lithium as a drug on the protein interaction network of GSK-3β as a hub protein and computed the affinities of GSK-3β to its partners in the presence of lithium or sodium ions. For this purpose, ensembles of GSK-3β protein structures were created in the presence of either lithium or sodium ions using adaptive tempering molecular dynamics simulations. The protein binding patches of GSK-3β for its partners were determined, and finally, the affinity of each binding patch to the related partner was computed for structures of ensembles using a monomer-based approach. Besides, by comparing structural dynamics of GSK-3β during MD simulations in the presence of LiCl and NaCl, we suggested a new mechanism for the inhibitory effect of lithium on GSK-3β.