TY - JOUR
T1 - Computation of conformational transitions in proteins by virtual atom molecular mechanics as validated in application to adenylate kinase
AU - Korkut, Anil
AU - Hendricksona, Wayne A.
PY - 2009/9/15
Y1 - 2009/9/15
N2 - Many proteins function through conformational transitions between structurally disparate states, and there is a need to explore transition pathways between experimentally accessible states by computation. The sizes of systems of interest and the scale of conformational changes are often beyond the scope of full atomic models, but appropriate coarse-grained approaches can capture significant features. We have designed a comprehensive knowledge-based potential function based on a Cα representation for proteins that we call the virtual atom molecular mechanics (VAMM) force field. Here, we describe an algorithm for using the VAMM potential to describe conformational transitions, and we validate this algorithm in application to a transition between open and closed states of adenylate kinase (ADK). The VAMM algorithm computes normal modes for each state and iteratively moves each structure toward the other through a series of intermediates. The move from each side at each step is taken along that normal mode showing greatest engagement with the other state. The process continues to convergence of terminal intermediates to within a defined limit-here, a root-mean-square deviation of 1 Å. Validations show that the VAMM algorithm is highly effective, and the transition pathways examined for ADK are compatible with other structural and biophysical information. We expect that the VAMM algorithm can address many biological systems.
AB - Many proteins function through conformational transitions between structurally disparate states, and there is a need to explore transition pathways between experimentally accessible states by computation. The sizes of systems of interest and the scale of conformational changes are often beyond the scope of full atomic models, but appropriate coarse-grained approaches can capture significant features. We have designed a comprehensive knowledge-based potential function based on a Cα representation for proteins that we call the virtual atom molecular mechanics (VAMM) force field. Here, we describe an algorithm for using the VAMM potential to describe conformational transitions, and we validate this algorithm in application to a transition between open and closed states of adenylate kinase (ADK). The VAMM algorithm computes normal modes for each state and iteratively moves each structure toward the other through a series of intermediates. The move from each side at each step is taken along that normal mode showing greatest engagement with the other state. The process continues to convergence of terminal intermediates to within a defined limit-here, a root-mean-square deviation of 1 Å. Validations show that the VAMM algorithm is highly effective, and the transition pathways examined for ADK are compatible with other structural and biophysical information. We expect that the VAMM algorithm can address many biological systems.
KW - Coarse grained
KW - Potential function
KW - Transition pathways
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U2 - 10.1073/pnas.0907684106
DO - 10.1073/pnas.0907684106
M3 - Article
C2 - 19706894
AN - SCOPUS:70349462451
SN - 0027-8424
VL - 106
SP - 15673
EP - 15678
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 37
ER -