Molecular dynamics insights into protein‐glycosaminoglycan systems from microsecond‐scale simulations

Bojarski, Krzysztof K.; Sieradzan, Adam K.; Samsonov, Sergey A.

doi:10.1002/bip.23252

Cited by 35 publications

(39 citation statements)

References 52 publications

(70 reference statements)

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“…At the same time, the global minima for θ are different for the PMF data and the data from the microsecond‐scale MD simulation. This difference is very similar, both qualitatively and quantitatively (less than 2 kcal/mol), to the difference between the two minima of the PMF surfaces of a glycosidic linkage obtained from MD simulations expressed as functions of the ϕ and ψ angles (Figure ) discussed in this section, suggesting that, depending on the position of the glycosidic linkage in the heparin sequence, the position of the global minimum could be changed . It can be seen from Figure that these potentials are clearly not harmonic.…”

Section: Resultssupporting

confidence: 71%

“…However, the specific binding mode of a given GAG is likely to be selected because of the presence of polar side‐chains at a given binding site which can form additional H‐bonds with a GAG locking it in the binding mode. This is supported by the previous electrostatic potential calculations‐based analysis of heparin binding specificity in its complexes with antithrombin and basic fibroblast growth factor, which also suggested the key role of uncharged polar residues for the protein‐GAG recognition specificity (but no the affinity) in those systems . The H‐bonds are implicitly included in our CG model as the PMF calculations were performed in the explicit solvent in all‐atom MD simulations.…”

Section: Resultssupporting

confidence: 69%

“…Global preferences of these two minima obtained by umbrella sampling and in the unrestrained MD simulation are different by almost 2 kcal/mol. In this context, it is worth to mention that the differences of similar magnitude are also present in the data obtained for hexameric heparin in microsecond‐scale MD simulations for the same two minima of GlcNS(6S)‐IdoA(2S) glycosidic linkages depending on their sequential position in a heparin molecule in terms of their proximity to a reducing or nonreducing end . For IdoA(2S)‐GlcNS(6S), one minimum corresponding to ( ϕ , ψ ) value of (70, 140) was observed.…”

Section: Resultssupporting

confidence: 66%

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Local and long range potentials for heparin‐protein systems for coarse‐grained simulations

et al. 2019

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Heparin belongs to glycosaminoglycans (GAGs), a class of periodic linear anionic polysaccharides, which are functionally important components of the extracellular matrix owing to their interactions with various protein targets. Heparin is known to be involved in many cell signaling processes, while the experimental data available for heparin are significantly more abundant than for other GAGs. At the same time, the length and conformational flexibility of the heparin represent major challenges for its theoretical analysis. Coarse‐grained (CG) approaches, which enable us to extend the size‐ and time‐scale by orders of magnitude owing to reduction of system representation, appear, therefore, to be useful in simulating these systems. In this work, by using umbrella‐sampling molecular dynamics simulations, we derived and parameterized the CG backbone‐local potentials of heparin chains and the orientational potentials for the interactions of heparin with amino acid side chains to be further included in the physics‐based Unified Coarse‐Grained Model of biological macromolecules. With these potentials, simulations of extracellular matrix processes where both heparin and multiple proteins participate will be possible.

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Section: Resultssupporting

confidence: 71%

Section: Resultssupporting

confidence: 69%

Section: Resultssupporting

confidence: 66%

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Local and long range potentials for heparin‐protein systems for coarse‐grained simulations

et al. 2019

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“…The absolute binding free energy values thus ranged from -9.52 kcal/mol to -7.34 kcal/mol, given the uncertainties of different terms. In other words, our estimate for binding free energy is - kcal/mol to -106.1 kcal/mol 39 . The results obtained from the MM-GBSA approach are very different from our own SMD-BEUS results, which is to be expected given that MM-GBSA ignores various contributors to the free energy, such as the entropic change that arises from the protein-ligand interactions 40,43 .…”

Section: Modelmentioning

confidence: 72%

“…In addition to qualitative analysis of the complex, we have also quantified the hFGF1-heparin interaction in terms of its absolute binding free energy. Recent computational studies have attempted to calculate the binding free energy of the hFGF1-heparin complex using the MM-GBSA approach 39 .…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Picture for Monomeric Human Fibroblast Growth Factor 1 Stabilization by Heparin Binding

Kumar

Agrawal

Kumar

et al. 2020

Preprint

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Human fibroblast growth factor (FGF) 1 or hFGF1 is a member of the FGF family that isare involved in various vital processes such as cell proliferation, cell differentiation, angiogenesis and wound healing. hFGF1, which is associated with low stability in vivo, is known to be stabilized by binding heparin sulfate, a glycosaminoglycan that aids the protein in the activation of its cell surface receptor. The poor thermal and proteolytic stability of hFGF1 and the stabilizing role of heparin have long been observed experimentally; however, the mechanistic details of these phenomena either phenomenon are still not well understood. Here, we have used a combination of microsecond-level equilibrium molecular dynamics (MD) simulations, and state-of-the-art enhanced sampling MD simulations to quantitatively characterize the structural dynamics of monomeric hFGF1 in the presence and absence of heparin hexasaccharide. We have observed a local conformational changeconformational change in the heparin-binding pocketregion of hFGF1 that only occurs only in the absence of heparin. Several intramolecular hydrogen bonds were also identified within the heparin-binding pocket region, that form only when hFGF1 interacts with heparin. The loss of both intermolecular and intramolecular electrostatic interactions in the absence of heparin plausibly leads to the observed conformational change. This conformational transition results in increased flexibility of the heparin-binding pocket region and provides an explanation for the susceptibility of apo hFGF1 to proteolytic degradation and thermal instability . The hFGF1-heparin interactions) has also been quantified using absolute binding free energy calculations. Binding affinity (Kd) estimates determined computationally using our novel MD approach are in a good quantitative agreement with experimental Kd values from isothermal titration calorimetry experiments. The successful application of a combination of rigorous physics-based simulation techniques microsecond-level MD and accurate free energy calculations and its ability to accurately explain the biomolecular phenomena such as the heparin-mediated stabilization of hFGF1 at a quantitative level, provides open new opportunitiesrepresents a promising approach for studying complex towards understanding biological processesbiomolecular interactions between proteins and their binding partners at a detailed molecular level. using rigorous physics-based simulation techniques.

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Understanding Conformational Properties and Role of Hydrogen Bonds in Glycosaminoglycans‐Interleukin8 Complexes in Aqueous Medium by Molecular Dynamics Simulation

Dhurua

Jana

2022

ChemPhysChem

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Atomistic molecular dynamics simulations were performed under ambient conditions to explore the conformational features and binding affinities of hexameric glycosaminoglycans (GAGs) with chemokine Interleukin8 (IL8) in an aqueous medium. We tried to understand the role of hydrogen bonds (HBs) involving conserved water in mediating the interactions. The Luzar‐Chandler model was adopted to study the kinetics of HB breaking and formation concerning different water‐mediated HBs. The conformational flexibilities of bound GAGs are due to the flexible glycosidic linkages than the occasional/rare ring pucker conformation. The free energy landscape constructed with ϕ, and ψ, depicted that different conformational minima associated with the glycosidic linkage flexibility of the GAGs in bound states are separated by energy barriers. The binding affinities of IL8 towards GAGs are favored through the electrostatic and non‐polar solvation interactions. 4‐different types of conserved water were explored in the solvent‐mediated binding of GAGs with IL8. The average lifetime of the IL8‐GAG direct HB pairs was ∼ten times less than the IL8‐GAG‐shared water HBs. This is due to the rapid establishment of HB breaking and reformation kinetics involving water of a shared layer. We find that despite the highly negatively charged surface of GAGs, the IL8 surface populated by non‐cationic amino acids could serve as a promising binding site in addition to the cationic surface of the protein.

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Molecular dynamics insights into protein‐glycosaminoglycan systems from microsecond‐scale simulations

Cited by 35 publications

References 52 publications

Local and long range potentials for heparin‐protein systems for coarse‐grained simulations

Local and long range potentials for heparin‐protein systems for coarse‐grained simulations

Mechanistic Picture for Monomeric Human Fibroblast Growth Factor 1 Stabilization by Heparin Binding

Understanding Conformational Properties and Role of Hydrogen Bonds in Glycosaminoglycans‐Interleukin8 Complexes in Aqueous Medium by Molecular Dynamics Simulation

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