Constant pH molecular dynamics of proteins in explicit solvent with proton tautomerism

Goh, Garrett B.; Hulbert, Benjamin S.; Zhou, Huiqing; Brooks, Charles L.

doi:10.1002/prot.24499

Cited by 111 publications

(186 citation statements)

References 110 publications

Supporting

Mentioning

173

Contrasting

Order By: Relevance

“…In addition to the comparison with the experiment, the model used here was compared to different CpHMD approaches in more complex potential models with implicit solvent 66 and explicit solvent. 33 In both cases the NTL9 pK a values calculated by CpHMD C α SBM were very similar to those obtained via more complex simulations.…”

Section: Resultssupporting

confidence: 78%

“…For this comparison the definition of Goh et al was used. 33 The error in calculated pK a values is considered significant only in cases where the difference from the experimental pK a is higher than 1.0 pK a unit. In addition to the comparison with the experiment, the model used here was compared to different CpHMD approaches in more complex potential models with implicit solvent 66 and explicit solvent.…”

Section: Resultsmentioning

confidence: 99%

“…It is worthwhile noting that there are CpHMD studies in NTL9 protein, but they use different approaches with more complex potential models. 33,34 In the present study, CpHMD in C α SBM results are compared with experimental ones.…”

Section: Introductionmentioning

confidence: 96%

See 2 more Smart Citations

NTL9 Folding at Constant pH: The Importance of Electrostatic Interaction and pH Dependence

Contessoto

Oliveira

Carvalho

et al. 2016

J. Chem. Theory Comput.

View full text Add to dashboard Cite

The folding process of the N-terminal domain of ribosomal protein L9 (NTL9) was investigated at constant-pH computer simulations. Evaluation of the role of electrostatic interaction during folding was carried out by including a Debye-Hückel potential into a Cα structure-based model (SBM). In this study, the charges of the ionizable residues and the electrostatic potential are susceptible to the solution conditions, such as pH and ionic strength, as well as to the presence of charged groups. Simulations were performed under different pHs, and the results were validated by comparing them with experimental values of pKa and with denaturation experiment data. Also, the free energy profiles, Φ-values, and folding routes were calculated for each condition. It was shown how charges vary along the folding under different pH, which is subject to different scenarios. This study reveals how simplified models can capture essential physical features, reproducing experimental results, and presenting the role of electrostatic interactions before, during, and after the transition state.

show abstract

Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

NTL9 Folding at Constant pH: The Importance of Electrostatic Interaction and pH Dependence

Contessoto

Oliveira

Carvalho

et al. 2016

J. Chem. Theory Comput.

View full text Add to dashboard Cite

show abstract

“…By ensuring that n i and w i are greater than zero, one can impose monotonicity on N(B) approx . The sum of logistic functions has also been applied to describe pKa titration data 51 and constant pH simulations 44 for coupled proton sites. …”

Section: Grand Canonical Integrationmentioning

confidence: 99%

Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo

2015

View full text Add to dashboard Cite

Water molecules play integral roles in the formation of many protein-ligand complexes, and recent computational efforts have been focused on predicting the thermodynamic properties of individual waters and how they may be exploited in rational drug design. However, when water molecules form highly coupled hydrogen bonding networks, there is, as yet, no method that can rigorously calculate the free energy to bind the entire network, or assess the degree of cooperativity between waters. In this work, we report theoretical and methodological developments to the grand canonical Monte Carlo simulation technique. Central to our results is a rigorous equation that can be used to calculate efficiently the binding free energies of water networks of arbitrary size and complexity. Using a single set of simulations, our methods can locate waters, estimate their binding affinities, capture the cooperativity of the water network, and evaluate the hydration free energy of entire protein binding sites. Our techniques have been applied to multiple test systems and compare favourably to thermodynamic integra- *

show abstract

“…and calculated pK a values using pH titration fitting, which has been shown as a reliable and accurate approach to capture pK a values of protein residues in various systems (59)(60)(61)(62)(63)(64). Through the CPHMD modeling, we calculated the pK a of the possible pH-sensitive residues (Asp, Glu, and His) in the M, FI, dissociated E2 (Dis), and HT states.…”

Section: Significancementioning

confidence: 99%

Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion

Zhang

Mukhopadhyay

Brooks

2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Alphavirus envelope proteins, organized as trimers of E2-E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. In this work, we performed constant pH molecular dynamics based on an atomic model of the alphavirus envelope with icosahedral symmetry. We have identified pH-sensitive residues that cause the largest shifts in thermodynamic driving forces under neutral and acidic pH conditions for various fusion steps. A series of conserved interdomain His residues is identified to be responsible for the pH-dependent conformational changes in the fusion process, and ligand binding sites in their vicinity are anticipated to be potential drug targets aimed at inhibiting viral infections. 3). The lack of a vaccine or specific treatment prompts investigations of the fundamental mechanisms of the alphaviral lifecycle to facilitate the development of effective antiviral therapies (4). Alphaviruses have been reported to enter the cell through receptor-mediated endocytosis. Here, alphaviruses are ferried toward the perinuclear space of the host cell inside vesicles towed by molecular motors and delivered to specific locations for productive replication (5-11). Even when direct entry into the cytoplasm is possible (11-15), the endocytic entry pathway facilitates the transportation of viruses across the crowded cytoplasmic space and delays detection by the immune system without leaving empty capsid or envelope as obvious evidence of the viral infection exposed outside the host cell (10, 11). Before the delivery of its viral genome into the cytoplasm of a host cell, the alphavirus must undergo a critical step of low pH-triggered membrane fusion, which is a common mechanism in the endocytic viral entry pathway among many different viruses. Understanding the mechanism of the low pH-triggered alphaviral membrane fusion is essential for the development of therapies against alphavirus as well as other viruses using similar endocytic entry mechanisms.Recent studies of the lifecycle of alphavirus reveal that a precursor, p62, is first synthesized as a chaperon forming a heterodimer with E1, which is essential for viral budding (16); p62 protects the E1 protein in the low-pH environment of the secretory pathway before being cleaved by cellular furin to produce mature E2-E1 and a smaller fragment, E3 (17-21). After the virus buds from the cytoplasmic membrane, E3 is released from the virus particle under neutral pH conditions outside the host cell (13,(22)(23)(24).On the surface of a mature alphavirus, 80 (E2-E1) 3 viral spikes, organized in T = 4 icosahedral symmetry on the viral lipid membrane, enclose the viral capsid and genome (25-43). On internalization of the mature virus in the endosome of the host cell in a new round of infection cycle, the ...

show abstract

Constant pH molecular dynamics of proteins in explicit solvent with proton tautomerism

Cited by 111 publications

References 110 publications

NTL9 Folding at Constant pH: The Importance of Electrostatic Interaction and pH Dependence

NTL9 Folding at Constant pH: The Importance of Electrostatic Interaction and pH Dependence

Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo

Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion

Contact Info

Product

Resources

About