Langevin dynamics for the transport of flexible biological macromolecules in confined geometries

Peters, Michael

doi:10.1063/1.3525381

Cited by 6 publications

(9 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Broadly speaking, coarse-grained methods, stochastic dynamics, Brownian dynamics, and implicit solvent methods, are closely related terms representing macromolecular dynamic methods that involve some type of averaging method for the solvent phase. Here we simply refer to our method as implicit solvent or Brownian dynamics (BD) method [7-9]. Our first-principles method is comprehensive in that it includes all possible rotational, translational, and coupled rotational-translational modes of ligands (peptide amino acid residues in this study), quantitative limits on the use of BD methods via multiple time scale perturbation theory, inclusion of any external surfaces (protein molecular targets in this study), and formal, comprehensive prescription of all implicit solvent terms via time force autocorrelation expressions.…”

Section: Methodsmentioning

confidence: 99%

“…The macromolecular dynamics step requires Brownian particle diffusion terms and implicit solvent force terms that can be determined via the short-time behavior, or, alternatively, the diffusion and implicit solvent force terms can be approximated via separate analytical or computational studies for any given system, as demonstrated in proteins [8, 9]. Thus, BD has demonstrated the potential to greatly reduce the computational load required for protein dynamic simulations by reducing both the total atom-atom force computations load and increasing the integration time steps required.…”

Section: Methodsmentioning

confidence: 99%

“…Following previous studies [9], the apolar implicit solvent potential was taken to be proportional to the solvent accessible surface area with the surface tension parameter set to 0.5kcal/molA 2 . The solvent accessible surface area was calculated at the beginning of each Brownian dynamics step using the method of Hasel et al .…”

Section: Methodsmentioning

confidence: 99%

“…For the purposes of calculating the diffusion tensor, each ligand is modeled as a sphere in a continuum with an effective diameter based on their respective van der Waals volume [9]. The hydrodynamic interaction of the ligand with the receptor is neglected in all calculations given here.…”

Section: Methodsmentioning

confidence: 99%

“…Now, although the general algorithm can also include the flexibility of both ligand and receptor [9], the computational costs are currently prohibitive for this application, which necessarily involves the dynamic simulation of tens of thousands of ligands interacting with the target molecule. Consequently, all results given here are restricted to rigid ligands and receptors.…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

Targeting HIV-1 Envelope Proteins Using a Fragment Discovery All-Atom Computational Algorithm

Peters

2017

CEI

Self Cite

View full text Add to dashboard Cite

Introduction: HIV viral envelope proteins are targets for small inhibitor molecules aimed at disrupting the cellular entry process. Potential peptide-class inhibitor molecules (rDNA drugs) have been previously identified, with mixed results, through biomimicry and phage display experimental methods. Here we describe a new approach based on computational fragment discovery. The method has the potential to not only optimize peptide binding affinity but also to rapidly produce alternative inhibitors against mutated strains. Methods: A comprehensive, all-atom implicit solvent method is used to bombard the C-heptad repeat unit of HIV-1 target envelope protein GP41 with single Damino acid residues as they exist in their native state. A nascent peptide computational search process then identifies potential favorable sequences of attached ligands based on four peptide bond criteria. Finally, dynamic simulations of nascent peptides attached to host targets help refine potential peptide inhibitors for experimental HIV-1 challenge assays and testing. Results and Discussion: Initial testing of the method was done using 64,000 total ligands of D-amino acid residues at a total computational time of 0.05 microseconds per ligand, which resulted in several thousand attached ligands. Peptide bond criteria search employing three of the four bond constraints with a tolerance of 20 percent, resulted in four potential peptide inhibitors of 5 to 6 residues in length. Only one of the four peptides demonstrated IC50 values and partial viral inhibition based on cell challenge assays using CEM-SS host cells. That peptide inhibitor also computationally demonstrated longtime attachment and stability to a helical groove in its C-heptad target. This initial testing of peptide fragment discovery against HIV-1 has helped us refine the protocols and identify key areas of improvement. Conclusion: Our methods demonstrate the potential to design efficient peptide inhibitors to viral target proteins based on an all-atom dynamic simulation and using a ligand library as fragments of potential nascent peptides. Our methods can be greatly improved through the use of higher numbers of ligands, increased time of bombardment, and tighter constraints on the peptide bond search step. Our method may be important in the need to rapidly respond to target mutations and to advance multiple targeting methods based multiple peptide inhibitors.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations