期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 101, 期 12, 页码 4444-4457出版社
WILEY-BLACKWELL
DOI: 10.1002/jps.23332
关键词
proteins; immunoglobulins; local dynamics; protein structure; stability; excipients; fluorescence spectroscopy
资金
- MedImmune
A molecular understanding of excipient effects on the interrelationship(s) between dynamics and conformational stability of proteins, such as monoclonal antibodies (mAbs), can be important for their pharmaceutical development. The current study examines stabilizing and destabilizing effects of excipients on the conformational stability and local dynamics of distinct solvent-exposed regions within an IgG1 monoclonal antibody (mAb-B). The principles of site-selective photoselection upon red-edge excitation, accompanied by acrylamide quenching of tryptophan fluorescence were employed in this study. The initiation of mAb-B thermal unfolding occurs by structural alterations in the more solvent-exposed regions of the antibody, which subsequently leads to a cascade of structural alterations in its relatively more solvent-shielded regions. In addition, an increase in internal dynamics of solvent-shielded regions made mAb-B more susceptible to thermally induced structural perturbations resulting in its global destabilization. Sucrose and arginine exert their stabilizing and destabilizing effects by predominantly influencing the conformational stability of solvent-exposed regions in mAb-B. The complex molecular effects of sucrose and arginine on local dynamics of different regions in mAb-B and their correlation with the protein's conformational stability are described within the pretransition range, at the onset temperature (Tonset) and at the thermal melting temperature (TM). (c) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:44444457, 2012
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据