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Role of Counterions in Constant-pH Molecular Dynamics Simulations of PAMAM Dendrimers.

ABSTRACT: Electrostatic interactions play a pivotal role in the structure and mechanism of action of most biomolecules. There are several conceptually different methods to deal with electrostatics in molecular dynamics simulations. Ionic strength effects are usually introduced using such methodologies and can have a significant impact on the quality of the final conformation space obtained. We have previously shown that full system neutralization can lead to wrong lipidic phases in the 25% PA/PC bilayer (J. Chem. Theory Comput. 2014,10, 5483-5492). In this work, we investigate how two limit approaches to the ionic strength treatment (implicitly with GRF or using full system neutralization with either GRF or PME) can influence the conformational space of the second-generation PAMAM dendrimer. Constant-pH MD simulations were used to map PAMAM's conformational space at its full pH range (from 2.5 to 12.5). Our simulations clearly captured the coupling between protonation and conformation in PAMAM. Interestingly, the dendrimer conformational distribution was almost independent of the ionic strength treatment methods, which is in contrast to what we have observed in charged lipid bilayers. Overall, our results confirm that both GRF with implicit ionic strength and a fully neutralized system with PME are valid approaches to model charged globular systems, using the GROMOS 54A7 force field.

SUBMITTER: Reis PBPS

PROVIDER: S-EPMC6045380 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Role of Counterions in Constant-pH Molecular Dynamics Simulations of PAMAM Dendrimers.

Reis Pedro B P S PBPS Vila-Viçosa Diogo D Campos Sara R R SRR Baptista António M AM Machuqueiro Miguel M

ACS omega 20180219 2

Electrostatic interactions play a pivotal role in the structure and mechanism of action of most biomolecules. There are several conceptually different methods to deal with electrostatics in molecular dynamics simulations. Ionic strength effects are usually introduced using such methodologies and can have a significant impact on the quality of the final conformation space obtained. We have previously shown that full system neutralization can lead to wrong lipidic phases in the 25% PA/PC bilayer ( ...[more]

PMID: 30023821

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Project description:We present a GPU implementation of the continuous constant pH molecular dynamics (CpHMD) based on the most recent generalized Born implicit-solvent model in the pmemd engine of the Amber molecular dynamics package. To test the accuracy of the tool for rapid pKa predictions, a series of 2 ns single-pH simulations were performed for over 120 titratable residues in 10 benchmark proteins that were previously used to test the various continuous CpHMD methods. The calculated pKa's showed a root-mean-square deviation of 0.80 and correlation coefficient of 0.83 with respect to experiment. Also, 90% of the pKa's were converged with estimated errors below 0.1 pH units. Surprisingly, this level of accuracy is similar to our previous replica-exchange simulations with 2 ns per replica and an exchange attempt frequency of 2 ps-1 (Huang, Harris, and Shen J. Chem. Inf. Model. 2018 , 58 , 1372 - 1383 ). Interestingly, for the linked titration sites in two enzymes, although residue-specific protonation state sampling in the single-pH simulations was not converged within 2 ns, the protonation fraction of the linked residues appeared to be largely converged, and the experimental macroscopic pKa values were reproduced to within 1 pH unit. Comparison with replica-exchange simulations with different exchange attempt frequencies showed that the splitting between the two macroscopic pKa's is underestimated with frequent exchange attempts such as 2 ps-1, while single-pH simulations overestimate the splitting. The same trend is seen for the single-pH vs replica-exchange simulations of a hydrogen-bonded aspartyl dyad in a much larger protein. A 2 ns single-pH simulation of a 400-residue protein takes about 1 h on a single NVIDIA GeForce RTX 2080 graphics card, which is over 1000 times faster than a CpHMD run on a single CPU core of a high-performance computing cluster node. Thus, we envision that GPU-accelerated continuous CpHMD may be used in routine pKa predictions for a variety of applications, from assisting MD simulations with protonation state assignment to offering pH-dependent corrections of binding free energies and identifying reactive hot spots for covalent drug design.

Dataset Information

Role of Counterions in Constant-pH Molecular Dynamics Simulations of PAMAM Dendrimers.

Publications

Role of Counterions in Constant-pH Molecular Dynamics Simulations of PAMAM Dendrimers.

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