Conserved Hydration Sites in Pin1 Reveal a Distinctive Water Recognition Motif in Proteins

Barman, Arghya; Smitherman, Crystal; Souffrant, Michael; Gadda, Giovanni; Hamelberg, Donald

doi:10.1021/acs.jcim.5b00560

Cited by 5 publications

(5 citation statements)

References 63 publications

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“…A significant number of experimental and computational studies have been carried out to understand the catalytic mechanism and function of Pin1. ,− However, very little is known about the role of the WW domain in the allosteric regulation of Pin1. , The molecular basis of the allosteric mechanism of Pin1 remains elusive and therefore requires a full atomic level description of the full length Pin1 to separate out the role of the WW domain. Experimentally, the effect of the binding of the substrate to the WW domain on the mechanism of the wild type would be hard to separate out, since a natural substrate would inherently bind to both domains.…”

Section: Introductionmentioning

confidence: 99%

Coupled Dynamics and Entropic Contribution to the Allosteric Mechanism of Pin1

Barman

Hamelberg

2016

J. Phys. Chem. B

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Allosteric communication in proteins regulates a plethora of downstream processes in subcellular signaling pathways. Describing the effects of cooperative ligand binding on the atomic level is a key to understanding many regulatory processes involving biomolecules. Here, we use microsecond-long molecular dynamics simulations to investigate the allosteric mechanism of Pin1, a potential therapeutic target and a phosphorylated-Ser/Thr dependent peptidyl-prolyl cis-trans isomerase that regulates several subcellular processes and has been implicated in many diseases, including cancer and Alzheimer's. Experimental studies suggest that the catalytic domain and the noncatalytic WW domain are allosterically coupled; however, an atomic level description of the dynamics associated with the interdomain communication is lacking. We show that binding of the substrate to the WW domain is directly coupled to the dynamics of the catalytic domain, causing rearrangement of the residue-residue contact dynamics from the WW domain to the catalytic domain. The binding affinity of the substrate in the catalytic domain is also enhanced upon binding of the substrate to the WW domain. Modulation of the dynamics of the catalytic domain upon binding of the substrate to the WW domain leads to prepayment of the entropic cost of binding the substrate to the catalytic domain. This study shows that Ile 28 at the interfacial region between the catalytic and WW domains is certainly one of the residues responsible for bridging the communication between the two domains. The results complement previous experiments and provide valuable atomistic insights into the role of dynamics and possible entropic contribution to the allosteric mechanism of proteins.

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Section: Introductionmentioning

confidence: 99%

Coupled Dynamics and Entropic Contribution to the Allosteric Mechanism of Pin1

Barman

Hamelberg

2016

J. Phys. Chem. B

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“…In another enzyme class, two conserved water molecules that play a structural role have been observed in the catalytic domain of Pin1, an enzyme that catalyzes the cis / trans isomerization of peptidyl prolyl bonds. A careful investigation using both computational and spectroscopic methods highlighted a unique structural motif that traps water molecules, similar to that observed for the EF-hand domain for calcium . In another example, DNA methyltransferases, key enzymes in the epigenetic pattern of DNA, have attracted great interest because their role in cell replication suggests a potential strategy for anticancer drug development.…”

Section: Thermodynamics From Water’s Point Of View: Hot and Cold Watermentioning

confidence: 99%

The Roles of Water in the Protein Matrix: A Largely Untapped Resource for Drug Discovery

et al. 2017

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The value of thoroughly understanding the thermodynamics specific to a drug discovery/design study is well known. Over the past decade, the crucial roles of water molecules in protein structure, function, and dynamics have also become increasingly appreciated. This Perspective explores water in the biological environment by adopting its point of view in such phenomena. The prevailing thermodynamic models of the past, where water was seen largely in terms of an entropic gain after its displacement by a ligand, are now known to be much too simplistic. We adopt a set of terminology that describes water molecules as being "hot" and "cold", which we have defined as being easy and difficult to displace, respectively. The basis of these designations, which involve both enthalpic and entropic water contributions, are explored in several classes of biomolecules and structural motifs. The hallmarks for characterizing water molecules are examined, and computational tools for evaluating water-centric thermodynamics are reviewed. This Perspective's summary features guidelines for exploiting water molecules in drug discovery.

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“…[29][30][31][32][33] Structural similarity among members of protein families has been found to often entail the conservation of internal hydration sites. [34][35][36][37][38][39] PKs are no different in this respect. Conserved, specific water network within ATP binding site was identified in a number of early crystal structures of protein kinase A (PKA).…”

Section: Introductionmentioning

confidence: 99%

“…Structural similarity among members of protein families has been found to often entail the conservation of internal hydration sites 34‐39 . PKs are no different in this respect.…”

Section: Introductionmentioning

confidence: 99%

Conserved internal hydration motifs in protein kinases

Setny

2020

Proteins

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Crystal structures of diverse protein kinase catalytic subunits reveal a number of water molecules whose positions within the protein core are better preserved than amino acid types in many functionally important locations. It remains unknown whether they play any particular role, and whether their removal, disturbing local interaction patterns to no smaller degree than amino acid mutations, can affect kinase stability and function. In this study, we apply an array of computational approaches to characterize hydration of kinase catalytic subunits. First, we systematically screen multiple crystal structures with the use of a simplified hydration model in order to determine the distribution of internal solvent and the degree of its conservation. Second, we analyze water structure, dynamics and binding affinity to buried hydration sites in a number of kinases, also taking into account their variable functional state. We find that a large portion of buried solvent is dynamic, possibly contributing to kinase conformational changes related to the activation process. In turn, binding free energies of some of tightly bound conserved water molecules to different kinases tend to shift in a similar manner following the change of their functional state. This finding highlights the likely specific role of internal solvent in fine tuning local protein plasticity.

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Conserved Hydration Sites in Pin1 Reveal a Distinctive Water Recognition Motif in Proteins

Cited by 5 publications

References 63 publications

Coupled Dynamics and Entropic Contribution to the Allosteric Mechanism of Pin1

Coupled Dynamics and Entropic Contribution to the Allosteric Mechanism of Pin1

The Roles of Water in the Protein Matrix: A Largely Untapped Resource for Drug Discovery

Conserved internal hydration motifs in protein kinases

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