Interdomain dynamics in human Replication Protein A regulates kinetics and thermodynamics of its binding to ssDNA

Human Replication Protein A (hRPA) is a multidomain protein that interacts with ssDNA intermediates to provide the latter much-needed stability during DNA metabolism and maintain genomic integrity. Although the ssDNA organization with hRPA was studied recently through experimental means, characteriz...

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description Human Replication Protein A (hRPA) is a multidomain protein that interacts with ssDNA intermediates to provide the latter much-needed stability during DNA metabolism and maintain genomic integrity. Although the ssDNA organization with hRPA was studied recently through experimental means, characterizing the underlying mechanism at the atomic level remains challenging because of the dynamic domain architecture of hRPA and poorly understood heterogeneity of ssDNA-protein interactions. Here, we used a computational framework, precisely tailored to capture protein-ssDNA interactions, and investigated the binding of hRPA with a 60 nt ssDNA. Two distinct binding mechanisms are realized based on the hRPA domain flexibility. For a rigid domain architecture of hRPA, ssDNA binds sequentially with hRPA domains, resulting in slow association kinetics. The binding pathway involves the formation of stable and distinct intermediate states. On contrary, for a flexible domain architecture of hRPA, ssDNA binds synergistically to the A and B domains followed by the rest of hRPA. The domain dynamics in hRPA alleviates the free energy cost of domain orientation necessary for specific binding with ssDNA, leading to fast association kinetics along a downhill binding free energy landscape. An ensemble of free energetically degenerate intermediate states is encountered that makes it arduous to characterize them structurally. An excellent match between our results with the available experimental observations provides new insights into the rich dynamics of hRPA binding to ssDNA and in general paves the way to investigate intricate details of ssDNA-protein interactions, crucial for cellular functioning.
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subjects Architecture
Binding
Biology and Life Sciences
Computer applications
Deoxyribonucleic acid
DNA
DNA binding proteins
DNA, Single-Stranded
Domains
Energy costs
Free energy
Heterogeneity
Humans
Intermediates
Kinetics
Metabolism
Physical Sciences
Physiological aspects
Protein A
Protein binding
Protein Binding - genetics
Protein interaction
Protein research
Protein-protein interactions
Proteins
Proteins - metabolism
Replication
Replication protein A
Replication Protein A - metabolism
Structure
Thermodynamics
title Interdomain dynamics in human Replication Protein A regulates kinetics and thermodynamics of its binding to ssDNA
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