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Conformational dynamics of HIV-1 protease: a comparative molecular dynamics simulation study with multiple amber
Biswa Ranjan Meher1, Mattaparthi Venkata Satish Kumar, Smriti Sharma
1Computational Biology Research Laboratory, Department of Biotechnology, Indian Institute of Technology, Guwahati, Assam 781039, India. brmeher@gmail.com
Journal of Bioinformatics and Computational Biology
|August 1, 2012
Summary
The ff99SB and ff03 force fields accurately model HIV-1 protease flap dynamics compared to NMR data. The ff03 force field shows increased loop flexibility, potentially impacting drug design for flexible receptors.
Area of Science:
- Biophysics
- Computational Chemistry
- Structural Biology
Background:
- HIV-1 protease (HIV-pr) flap dynamics are crucial for inhibitor and substrate access to the active site.
- Previous dynamical models of HIV-pr lack consistency and experimental NMR support.
- Accurate force fields are essential for reliable molecular dynamics (MD) simulations of protein dynamics.
Purpose of the Study:
- To investigate the influence of different AMBER force fields on the dynamics of HIV-1 protease.
- To compare simulation-derived generalized order parameters with experimental NMR S2 values.
- To assess the impact of force field choice on HIV-pr active site flexibility and implications for drug design.
Main Methods:
- Molecular dynamics (MD) simulations of HIV-1 protease using three AMBER force fields: ff99, ff99SB, and ff03.
- Calculation of generalized order parameters for the protein's amide backbone from simulation trajectories.
- Comparison of calculated order parameters with experimentally determined NMR S2 values.
Main Results:
- The ff99SB and ff03 force fields demonstrated good agreement with NMR S2 values for HIV-pr dynamics.
- The ff99 force field showed significant deviations from experimental NMR data.
- The ff03 force field exhibited increased flexibility in loop regions, leading to a larger active site cavity compared to ff99SB.
Conclusions:
- The ff99SB and ff03 force fields provide more reliable representations of HIV-1 protease flap dynamics than ff99.
- Differences in loop flexibility between ff99SB and ff03, particularly with ff03, may influence the efficacy of computer-aided drug design targeting flexible receptors.
- Further investigation into force field effects is warranted for optimizing drug discovery strategies against HIV-pr.
