Biomaterial Database

Simulated mutagenesis of the hypervariable loops of a llama VHH domain for the recovery of canonical conformations. 2009

Camilo Velez-Vega, and Michael K Fenwick, and Fernando A Escobedo

School of Chemical and Biomolecular Engineering, Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.

In this work, wildtype and mutated hypervariable regions of an anti-hCG llama VHH antibody were simulated via a molecular dynamics replica exchange method (REM). Seven mutants were simulated with the goal of identifying structural determinants that return the noncanonical H1 loop of the wildtype antibody to the type 1 canonical structure predicted by database methods formulated for conventional antibodies. Two cases with three point mutations yielded a stable type 1 H1 structure. In addition, other mutants with fewer mutations showed evidence of such conformations. Overall, the mutagenesis results suggest a marked influence of interloop interactions on the attainment of canonical conformations for this antibody. On the methodological front, a novel REM scheme was developed to quickly screen diverse mutants based on their relative propensities for attaining favorable structures. This multimutant REM (MMREM) was used to successfully identify mutations that stabilize a canonical H1 loop grafted on the llama antibody scaffold. The use of MMREM and REM for screening mutants and assessing structural stability may be useful in the rational design of antibody hypervariable loops.

UI	MeSH Term	Description	Entries
D007143	Immunoglobulin Heavy Chains	The largest of polypeptide chains comprising immunoglobulins. They contain 450 to 600 amino acid residues per chain, and have molecular weights of 51-72 kDa.	Immunoglobulins, Heavy-Chain,Heavy-Chain Immunoglobulins,Ig Heavy Chains,Immunoglobulin Heavy Chain,Immunoglobulin Heavy Chain Subgroup VH-I,Immunoglobulin Heavy Chain Subgroup VH-III,Heavy Chain Immunoglobulins,Heavy Chain, Immunoglobulin,Heavy Chains, Ig,Heavy Chains, Immunoglobulin,Immunoglobulin Heavy Chain Subgroup VH I,Immunoglobulin Heavy Chain Subgroup VH III,Immunoglobulins, Heavy Chain
D008958	Models, Molecular	Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.	Molecular Models,Model, Molecular,Molecular Model
D009682	Magnetic Resonance Spectroscopy	Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING).	In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D011487	Protein Conformation	The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).	Conformation, Protein,Conformations, Protein,Protein Conformations
D002161	Camelids, New World	Camelidae of the Americas. The extant species are those originating from South America and include alpacas, llamas, guanicos, and vicunas.	Alpacas,Guanacos,Llamas,Lama glama,Lama glama guanicoe,Lama guanicoe,Lama pacos,Vicugna pacos,Vicugna vicugna,Vicunas,Alpaca,Camelid, New World,Guanaco,Llama,New World Camelid,New World Camelids,Vicuna
D003198	Computer Simulation	Computer-based representation of physical systems and phenomena such as chemical processes.	Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000906	Antibodies	Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the ANTIGEN (or a very similar shape) that induced their synthesis in cells of the lymphoid series (especially PLASMA CELLS).
D013997	Time Factors	Elements of limited time intervals, contributing to particular results or situations.	Time Series,Factor, Time,Time Factor
D016296	Mutagenesis	Process of generating a genetic MUTATION. It may occur spontaneously or be induced by MUTAGENS.	Mutageneses