Abstract
Molecular dynamics (MD) simulation is an important tool for understanding bio-molecules in microscopic temporal/spatial scales. Besides the demand in improving simulation techniques to approach experimental scales, it becomes more and more crucial to develop robust methodology for precisely and objectively interpreting massive MD simulation data. In our previous work [J Phys Chem B 114, 10266 (2010)], the trajectory mapping (TM) method was presented to analyze simulation trajectories then to construct a kinetic transition network of metastable states. In this work, we further present a top-down implementation of TM to systematically detect complicate features of conformational space. We first look at longer MD trajectory pieces to get a coarse picture of transition network at larger time scale, and then we gradually cut the trajectory pieces in shorter for more details. A robust clustering algorithm is designed to more effectively identify the metastable states and transition events. We applied this TM method to detect the hierarchical structure in the conformational space of alanine-dodeca-peptide from microsecond to nanosecond time scales. The results show a downhill folding process of the peptide through multiple pathways. Even in this simple system, we found that single common-used order parameter is not sufficient either in distinguishing the metastable states or predicting the transition kinetics among these states.
Highlights
Protein folding problem has been intensively studied for decades
We calculated the similarity between the conformational distributions of these long trajectories, i. e. the scaled inner product (SIP) defined in Eq (6)
The results are shown in Supporting Information as S3 Fig. every simulation trajectory partially overlaps with some others, there do not exist two simulation trajectories very similar to each other such that their SIP is close to one
Summary
Protein folding problem has been intensively studied for decades. in-depth understanding of proteins has been established by the pioneer works, see reference [1] for brief review, due to the tremendous complexity of these molecules, there is still a long way to get a clear and definitive description of conformational motions in proteins.The current progress of experimental and simulation methods has made the protein structural ensemble accessible to researchers. Protein folding problem has been intensively studied for decades. In-depth understanding of proteins has been established by the pioneer works, see reference [1] for brief review, due to the tremendous complexity of these molecules, there is still a long way to get a clear and definitive description of conformational motions in proteins. The current progress of experimental and simulation methods has made the protein structural ensemble accessible to researchers. It is possible to directly observe the protein conformational dynamics by single molecular fluorescence method (SMF) [2]. The full details of protein dynamics can be obtained by molecular dynamics (MD).
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