Molecular Docking and Molecular Dynamics (MD) Simulation of Human Anti-Complement Factor H (CFH) Antibody Ab42 and CFH Polypeptide

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Abstract

An understanding of the interaction between the antibody and its targeted antigen and knowing of the epitopes are critical for the development of monoclonal antibody drugs. Complement factor H (CFH) is implied to play a role in tumor growth and metastasis. An autoantibody to CHF is associated with anti-tumor cell activity. The interaction of a human monoclonal antibody Ab42 that was isolated from a cancer patient with CFH polypeptide (pCFH) antigen was analyzed by molecular docking, molecular dynamics (MD) simulation, free energy calculation, and computational alanine scanning (CAS). Experimental alanine scanning (EAS) was then carried out to verify the results of the theoretical calculation. Our results demonstrated that the Ab42 antibody interacts with pCFH by hydrogen bonds through the Tyr315, Ser100, Gly33, and Tyr53 residues on the complementarity-determining regions (CDRs), respectively, with the amino acid residues of Pro441, Ile442, Asp443, Asn444, Ile447, and Thr448 on the pCFH antigen. In conclusion, this study has explored the mechanism of interaction between Ab42 antibody and its targeted antigen by both theoretical and experimental analysis. Our results have important theoretical significance for the design and development of relevant antibody drugs.

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Complement control protein factor H: the good, the bad, and the inadequate.

Viviana Ferreira, Michael Pangburn, Claudio Cortés (2010)

The complement system is an essential component of the innate immune system that participates in elimination of pathogens and altered host cells and comprises an essential link between the innate and adaptive immune system. Soluble and membrane-bound complement regulators protect cells and tissues from unintended complement-mediated injury. Complement factor H is a soluble complement regulator essential for controlling the alternative pathway in blood and on cell surfaces. Normal recognition of self-cell markers (i.e. polyanions) and C3b/C3d fragments is necessary for factor H function. Inadequate recognition of host cell surfaces by factor H due to mutations and polymorphisms have been associated with complement-mediated tissue damage and disease. On the other hand, unwanted recognition of pathogens and altered self-cells (i.e. cancer) by factor H is used as an immune evasion strategy. This review will focus on the current knowledge related to these versatile recognition properties of factor H. Copyright 2010 Elsevier Ltd. All rights reserved.

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ZRANK: reranking protein docking predictions with an optimized energy function.

Brian G Pierce, Zhiping Weng (2007)

Protein-protein docking requires fast and effective methods to quickly discriminate correct from incorrect predictions generated by initial-stage docking. We have developed and tested a scoring function that utilizes detailed electrostatics, van der Waals, and desolvation to rescore initial-stage docking predictions. Weights for the scoring terms were optimized for a set of test cases, and this optimized function was then tested on an independent set of nonredundant cases. This program, named ZRANK, is shown to significantly improve the success rate over the initial ZDOCK rankings across a large benchmark. The amount of test cases with No. 1 ranked hits increased from 2 to 11 and from 6 to 12 when predictions from two ZDOCK versions were considered. ZRANK can be applied either as a refinement protocol in itself or as a preprocessing stage to enrich the well-ranked hits prior to further refinement. 2007 Wiley-Liss, Inc.

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Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA.

P. Morin, Daphne Wang, J. Wang … (2001)

In this work, a new ansatz is presented that combines molecular dynamics simulations with MM-PBSA (Molecular Mechanics Poisson-Boltzmann/surface area) to rank the binding affinities of 12 TIBO-like HIV-1 RT inhibitors. Encouraging results have been obtained not only for the relative binding free energies, but also for the absolute ones, which have a root-mean-square deviation of 1.0 kcal/mol (the maximum error is 1.89 kcal/mol). Since the root-mean-square error is rather small, this approach can be reliably applied in ranking the ligands from the databases for this important target. Encouraged by the results, we decided to apply MM-PBSA combined with molecular docking to determine the binding mode of efavirenz SUSTIVA(TM) another promising HIV-1 RT inhibitor for which no ligand-protein crystal structure had been published at the time of this work. To proceed, we define the following ansatz: Five hundred picosecond molecular dynamics simulations were first performed for the five binding modes suggested by DOCK 4.0, and then MM-PBSA was carried out for the collected snapshots. MM-PBSA successfully identified the correct binding mode, which has a binding free energy about 7 kcal/mol more favorable than the second best mode. Moreover, the calculated binding free energy (-13.2 kcal/mol) is in reasonable agreement with experiment (-11.6 kcal/mol). In addition, this procedure was also quite successful in modeling the complex and the structure of the last snapshot was quite close to that of the measured 2,3 A resolution crystal (structure the root-mean-square deviation of the 54 C(alpha) around the binding site and the inhibitor is 1.1 A). We want to point out that this result was achieved without prior knowledge of the structure of the efavirenz/RT complex. Therefore, molecular docking combined with MD simulations followed by MM-PBSA analysis is an attractive approach for modeling protein complexes a priori.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 25 May 2019

Publication date Collection: May 2019

Volume: 20

Issue: 10

Electronic Location Identifier: 2568

Affiliations

[1 ]Institute of Biomedicine, Jinan University, Guangzhou 510632, China; candyYang_3940@ 123456163.com (B.Y.); linshujian18@ 123456163.com (S.-J.L.); liutong_smile@ 123456163.com (T.L.); ws_wym@ 123456126.com (Y.-M.W.); cli816@ 123456163.com (C.-M.L.); xuwenwen@ 123456jnu.edu.cn (W.-W.X.)

[2 ]Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China

[3 ]Zhuhai College of Jilin University, Zhuhai 519041, China; jiayi80@ 123456126.com

[4 ]National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China

[5 ]Department of Immunology, Duke University Medical Center, Durham, NC 27503, USA; youwen.he@ 123456duke.edu

[6 ]Zhuhai Trinomab Biotechnology Co., Ltd., Zhuhai 519040, China; zwh13901154411@ 123456139.com (W.-H.Z.); niezi581@ 123456163.com (J.Z.)

Author notes

[* ]Correspondence: yuanhui1024@ 123456gmail.com (X.-H.Y.); tliao805@ 123456jnu.edu.cn (H.-X.L.)

[†]

These authors contribute equally to this work.

Article

Publisher ID: ijms-20-02568

DOI: 10.3390/ijms20102568

PMC ID: 6566401

PubMed ID: 31130605

SO-VID: fd650dfd-f80a-4fab-9f89-1d03566396dc

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Molecular Docking and Molecular Dynamics (MD) Simulation of Human Anti-Complement Factor H (CFH) Antibody Ab42 and CFH Polypeptide

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Most cited references 34

Complement control protein factor H: the good, the bad, and the inadequate.

ZRANK: reranking protein docking predictions with an optimized energy function.

Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA.

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