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Computational Mutagenesis of Antibody Fragments: Disentangling Side Chains from ΔΔG Predictions.
Tandiana, Rika; Barletta, German P; Soler, Miguel Angel; Fortuna, Sara; Rocchia, Walter.
Afiliación
  • Tandiana R; Computational MOdelling of NanosCalE and BioPhysical SysTems─CONCEPT Lab Istituto Italiano di Tecnologia (IIT), Via Melen-83, B Block, 16152 Genoa, Italy.
  • Barletta GP; Computational MOdelling of NanosCalE and BioPhysical SysTems─CONCEPT Lab Istituto Italiano di Tecnologia (IIT), Via Melen-83, B Block, 16152 Genoa, Italy.
  • Soler MA; The Abdus Salam International Centre for Theoretical Physics─ICTP, Strada Costiera 11, 34151 Trieste, Italy.
  • Fortuna S; Dipartimento di Scienze Matematiche, Informatiche e Fisiche, Universita' di Udine, Via delle Scienze 206, 33100 Udine, Italy.
  • Rocchia W; Computational MOdelling of NanosCalE and BioPhysical SysTems─CONCEPT Lab Istituto Italiano di Tecnologia (IIT), Via Melen-83, B Block, 16152 Genoa, Italy.
J Chem Theory Comput ; 20(6): 2630-2642, 2024 Mar 26.
Article en En | MEDLINE | ID: mdl-38445482
ABSTRACT
The development of highly potent antibodies and antibody fragments as binding agents holds significant implications in fields such as biosensing and biotherapeutics. Their binding strength is intricately linked to the arrangement and composition of residues at the binding interface. Computational techniques offer a robust means to predict the three-dimensional structure of these complexes and to assess the affinity changes resulting from mutations. Given the interdependence of structure and affinity prediction, our objective here is to disentangle their roles. We aim to evaluate independently six side-chain reconstruction methods and ten binding affinity estimation techniques. This evaluation was pivotal in predicting affinity alterations due to single mutations, a key step in computational affinity maturation protocols. Our analysis focuses on a data set comprising 27 distinct antibody/hen egg white lysozyme complexes, each with crystal structures and experimentally determined binding affinities. Using six different side-chain reconstruction methods, we transformed each structure into its corresponding mutant via in silico single-point mutations. Subsequently, these structures undergo minimization and molecular dynamics simulation. We therefore estimate ΔΔG values based on the original crystal structure, its energy-minimized form, and the ensuing molecular dynamics trajectories. Our research underscores the critical importance of selecting reliable side-chain reconstruction methods and conducting thorough molecular dynamics simulations to accurately predict the impact of mutations. In summary, our study demonstrates that the integration of conformational sampling and scoring is a potent approach to precisely characterizing mutation processes in single-point mutagenesis protocols and crucial for computational antibody design.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Fragmentos de Inmunoglobulinas / Anticuerpos Idioma: En Revista: J Chem Theory Comput Año: 2024 Tipo del documento: Article País de afiliación: Italia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Fragmentos de Inmunoglobulinas / Anticuerpos Idioma: En Revista: J Chem Theory Comput Año: 2024 Tipo del documento: Article País de afiliación: Italia