Protein-Protein Interactions: Insight from Molecular Dynamics Simulations and Nanoparticle Tracking Analysis.

Wei Lim Chong,Piyarat Nimmanpipug,Vannajan Sanghiran Lee,Sook Mei Khor,Weeraya Thongkum,Sek Peng Chin,Mai Mai Khoo,Koollawat Chupradit,Chatchai Tayapiwatana

doi:10.3390/molecules26185696

Wei Lim Chong, Piyarat Nimmanpipug + Show 7 more

Open Access

https://doi.org/10.3390/molecules26185696

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Abstract

Protein-protein interaction plays an essential role in almost all cellular processes and biological functions. Coupling molecular dynamics (MD) simulations and nanoparticle tracking analysis (NTA) assay offered a simple, rapid, and direct approach in monitoring the protein-protein binding process and predicting the binding affinity. Our case study of designed ankyrin repeats proteins (DARPins)—AnkGAG1D4 and the single point mutated AnkGAG1D4-Y56A for HIV-1 capsid protein (CA) were investigated. As reported, AnkGAG1D4 bound with CA for inhibitory activity; however, it lost its inhibitory strength when tyrosine at residue 56 AnkGAG1D4, the most key residue was replaced by alanine (AnkGAG1D4-Y56A). Through NTA, the binding of DARPins and CA was measured by monitoring the increment of the hydrodynamic radius of the AnkGAG1D4-gold conjugated nanoparticles (AnkGAG1D4-GNP) and AnkGAG1D4-Y56A-GNP upon interaction with CA in buffer solution. The size of the AnkGAG1D4-GNP increased when it interacted with CA but not AnkGAG1D4-Y56A-GNP. In addition, a much higher binding free energy (∆GB) of AnkGAG1D4-Y56A (−31 kcal/mol) obtained from MD further suggested affinity for CA completely reduced compared to AnkGAG1D4 (−60 kcal/mol). The possible mechanism of the protein-protein binding was explored in detail by decomposing the binding free energy for crucial residues identification and hydrogen bond analysis.

Highlights

In almost all significant cellular processes and biological functions, protein-protein interactions play a vital role [1]
Binding free energy accounted from both methods agree with the experimental findings [36] in which AnkGAG1D4 lost its affinity toward capsid protein (CA) when tyrosine (Y) at position 56 was mutated to alanine (A)
Binding free energy computed by Molecular Mechanics Generalized Born Surface Area (MMGBSA) or Molecular Mechanics Poisson Boltzmann Surface Area (MMPBSA) algorithms have been widely employed to predict the binding affinity of protein-ligand [38,39,40,41] and protein-protein complexes [16,42,43,44] and is in good agreement with experimental findings

Summary

Introduction

In almost all significant cellular processes and biological functions, protein-protein interactions play a vital role [1]. Identifying protein-protein interactions and their binding affinity are crucial in knowing cellular biological processes, discovery and design of novel therapeutics, protein engineering, and mutagenesis studies [2]. Molecular dynamics (MD) simulation is one of the main in silico tool in the study of biomolecules owing to its better predictive power and more reliable analysis of protein structure, dynamics, and functions [7,8]. Simulating protein-protein interactions in the presence of water through molecular dynamics (MD) simulations has become a common, accurate and reliable approach in understanding the communication between the proteins. Dynamics and structure of protein obtained from MD simulations can be analyzed in depth to understand the interactions of the protein with its targets [7]

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