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Computational Methods for Calculation of Ligand-Receptor Binding Affinities Involving Protein and Nucleic Acid Complexes
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The ability to accurately predict binding free energies from computer simulations is an invaluable resource in understanding biochemical processes and drug action. Several methods based on microscopic molecular dynamics simulations exist, and in this thesis the validation, application, and development of the linear interaction energy (LIE) method is presented.

For a test case of several hydrophobic ligands binding to P450cam it is found that the LIE parameters do not change when simulations are performed with three different force fields. The nonpolar contribution to binding of these ligands is best reproduced with a constant offset and a previously determined scaling of the van der Waals interactions.

A new methodology for prediction of binding free energies of protein-protein complexes is investigated and found to give excellent agreement with experimental results. In order to reproduce the nonpolar contribution to binding, a different scaling of the van der Waals interactions is neccesary (compared to small ligand binding) and found to be, in part, due to an electrostatic preorganization effect not present when binding small ligands.

A new treatment of the electrostatic contribution to binding is also proposed. In this new scheme, the chemical makeup of the ligand determines the scaling of the electrostatic ligand interaction energies. These scaling factors are calibrated using the electrostatic contribution to hydration free energies and proposed to be applicable to ligand binding.

The issue of codon-anticodon recognition on the ribosome is adressed using LIE. The calculated binding free energies are in excellent agreement with experimental results, and further predict that the Leu2 anticodon stem loop is about 10 times more stable than the Ser stem loop in complex with a ribosome loaded with the Phe UUU codon. The simulations also support the previously suggested roles of A1492, A1493, and G530 in the codon-anticodon recognition process.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2007. , p. 53
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 255
Keywords [en]
Theoretical chemistry, computer simulations, molecular dynamics, linear interaction energy, binding free energy, linear response, protein-protein interactions, structure-based design, point mutations, hot spots, solvation free energy
Keywords [sv]
Teoretisk kemi
Identifiers
URN: urn:nbn:se:uu:diva-7421ISBN: 91-554-6761-X (print)OAI: oai:DiVA.org:uu-7421DiVA, id: diva2:169449
Public defence
2007-01-19, B7:101, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2006-12-22 Created: 2006-12-22Bibliographically approved
List of papers
1. Binding Affinity Prediction with Different Force Fields: Examination of the Linear Interaction Energy Method
Open this publication in new window or tab >>Binding Affinity Prediction with Different Force Fields: Examination of the Linear Interaction Energy Method
2004 In: Journal of Computational Chemistry, ISSN 0192-8651, Vol. 25, no 10, p. 1242-1254Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-95285 (URN)
Available from: 2006-12-22 Created: 2006-12-22Bibliographically approved
2. Probing the Effect of Point Mutations at Protein-Protein Interfaces with Free Energy Calculations
Open this publication in new window or tab >>Probing the Effect of Point Mutations at Protein-Protein Interfaces with Free Energy Calculations
2006 In: Biophysical Journal, ISSN 0006-3495, Vol. 90, no 2, p. 433-442Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-95286 (URN)
Available from: 2006-12-22 Created: 2006-12-22Bibliographically approved
3. Energetics of codon-anticodon recognition on the small ribosomal subunit
Open this publication in new window or tab >>Energetics of codon-anticodon recognition on the small ribosomal subunit
2007 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 1, p. 200-209Article in journal (Refereed) Published
Abstract [en]

Recent crystal structures of the small ribosomal subunit have made it possible to examine the detailed energetics of codon recognition on the ribosome by computational methods. The binding of cognate and near-cognate anticodon stem loops to the ribosome decoding center, with mRNA containing the Phe UUU and UUC codons, are analyzed here using explicit solvent molecular dynamics simulations together with the linear interaction energy (LIE) method. The calculated binding free energies are in excellent agreement with experimental binding constants and reproduce the relative effects of mismatches in the first and second codon position versus a mismatch at the wobble position. The simulations further predict that the Leu2 anticodon stem loop is about 10 times more stable than the Ser stem loop in complex with the Phe UUU codon. It is also found that the ribosome significantly enhances the intrinsic stability differences of codon-anticodon complexes in aqueous solution. Structural analysis of the simulations confirms the previously suggested importance of the universally conserved nucleotides A1492, A1493, and G530 in the decoding process.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-95287 (URN)10.1021/bi061713i (DOI)000243157300021 ()17198390 (PubMedID)
Available from: 2006-12-22 Created: 2006-12-22 Last updated: 2017-12-14Bibliographically approved
4. Investigation of the Linear Response Approximation for Predicting Hydration Free Energies
Open this publication in new window or tab >>Investigation of the Linear Response Approximation for Predicting Hydration Free Energies
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-95288 (URN)
Available from: 2006-12-22 Created: 2006-12-22 Last updated: 2010-01-13Bibliographically approved

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